Oxybenzamide derivatives useful for inhibiting factor Xa or viia

ABSTRACT

The present invention relates to compounds comprising the following formula:
 
R 0 —Q—X—Q′—W—U—V—G—M  (I)
 
These compounds are useful as pharmacologically active compounds. They exhibit an antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of cardiovascular disorders such as thromboembolic diseases or restenoses. These compounds are reversible inhibitors of the blood clotting enzymes factor Xa (FXa) and/or factor VIIa (FVIIa), and can generally be used to treat, prevent, or cure conditions in which an undesired activity of factor Xa and/or factor VIIa is present, or where inhibition of factor Xa and/or factor VIIa is intended. The invention further relates to processes for the preparation of these compounds, methods of their use (e.g., as active ingredients in pharmaceuticals), and pharmaceutical preparations comprising them.

DESCRIPTION OF THE INVENTION

The present invention relates to compounds of the formula I,R⁰—Q—X—Q′—W—U—V—G—M  (I)in which R⁰, Q, X, Q′, W, U, V, G, and M have the meanings indicatedbelow. The compounds of formula I are useful as pharmacologically activecompounds. They exhibit a strong antithrombotic effect and are suitable,for example, for the therapy and prophylaxis of cardiovascular disorderssuch as thromboembolic diseases or restenoses. These compounds arereversible inhibitors of the blood clotting enzymes factor Xa (FXa)and/or factor VIIa (FVIIa), and can generally be used to treat, prevent,or cure conditions in which an undesired activity of factor Xa and/orfactor VIIa is present or where inhibition of factor Xa and/or factorVIIa is intended. The invention furthermore relates to processes for thepreparation of compounds of the formula I, their use (e.g., as activeingredients in pharmaceuticals), and pharmaceutical preparationscomprising them.

Normal haemeostasis is the result of a complex balance between theprocesses of clot initiation, formation and clot dissolution. Thecomplex interactions between blood cells, specific plasma proteins andthe vascular surface maintain the fluidity of blood unless injury andblood loss occurs (EP-A-987274). Many significant disease states arerelated to abnormal haemeostasis. For example, local thrombus formationdue to rupture of atheroslerotic plaque is a major cause of acutemyocardial infarction and unstable angina. Treatment of an occlusivecoronary thrombus by either thrombolytic therapy or percutaneousangioplasty may be accompanied by acute thrombolytic reclosure of theaffected vessel.

There continues to be a need for safe and effective therapeuticanticoagulants to limit or prevent thrombus formation. Such agents mayinhibit coagulation without directly inhibiting thrombin. Instead ofinhibiting thrombin, they may inhibit other steps in the coagulationcascade like factor Xa and/or factor VIIa activity. It is now believedthat inhibitors of factor Xa carry a lower bleeding risk than thrombininhibitors (A. E. P. Adang & J. B. M. Rewinkel, Drugs of the Future2000, 25, 369-383).

Low molecular weight, factor Xa-specific blood clotting inhibitors thatare effective but do not cause unwanted side effects have beendescribed, for example, in WO-A-95/29189. However, besides beingeffective factor Xa-specific blood clotting inhibitors, it is desirablethat such inhibitors also have further advantageous properties; suchproperties include, for instance, stability in plasma and liver andselectivity versus other serine proteases whose inhibition is notintended, such as thrombin. Thus, there is an ongoing need in the artfor new low molecular weight factor-Xa specific blood clottinginhibitors, which are effective and also have one or more of the abovenoted advantages.

Specific inhibition of the factor VIIa/tissue factor catalytic complexusing monoclonal antibodies (WO-A-92/06711), or a protein such aschloromethyl ketone inactivated factor VIIa (WO-A-96/12800,WO-A-97/47651), is an extremely effective means of controlling thrombusformation caused by acute arterial injury or the thromboticcomplications related to bacterial septicaemia. There is alsoexperimental evidence suggesting that inhibition of factor VIIa/tissuefactor activity inhibits restenosis following balloon angioplasty.Bleeding studies conducted in baboons indicate that inhibition of thefactor VIIa/tissue factor complex has the widest safety window withrespect to therapeutic effectiveness and bleeding risk of anyanticoagulant approach tested including thrombin, platelet and factor Xainhibition. Certain inhibitors of factor VIIa have been described. Forexample, EP-A-987274 describes compounds containing a tripeptide unitthat inhibit factor VIIa. However, the property profile of thesecompounds is less than ideal, and there remains an ongoing need forfurther low molecular weight factor VIIa-specific blood clottinginhibitors.

The present invention satisfies the above needs by providing novelcompounds of formula I, which exhibit factor Xa and/or factor VIIainhibitory activity and are favourable agents for inhibiting unwantedblood clotting and thrombus formation.

Thus, the present invention relates to compounds of the formula I,R⁰—Q—X—Q′—W—U—V—G—M  (I)wherein

-   R⁰ is    -   1. a monocyclic or bicyclic 5- to 14-membered aryl, wherein aryl        is unsubstituted or mono-, di- or trisubstituted independently        of one another by R², or    -   2. a monocyclic or bicyclic 5- to 14-membered heteroaryl,        containing zero, one, two, three or four heteroatoms chosen from        nitrogen, sulphur or oxygen, wherein heteroaryl is unsubstituted        or mono-, di- or trisubstituted independently of one another by        R²,-   R² is halogen, —NO₂, —CN, —C(O)—NH₂, —OH, —NH₂, —NH—C(O),    —NH—C(O)—(C₁-C₈)-alkyl, —NH—C(O)—(C₁-C₈)-alkyl, —(C₁-C₈)-alkyl,    wherein alkyl in each case is unsubstituted or mono-, di- or    trisubstituted independently of one another by halogen, NH₂, —OH or    a methoxy residue, or —(C₁-C₈)-alkyloxy, wherein alkyloxy is    unsubstituted or mono-, di- or trisubstituted independently of one    another by halogen, NH₂, —OH or a methoxy residue,-   Q and Q′ are independently of one another identical or different and    are a direct bond, —(CH₂)_(r)—O—CH₂)_(s)—, wherein r and s are    independently from each other the integers zero, 1, 2 or 3, —C(O)—;    —O—, —NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—, —S—, —S(O)—, —SO₂—,    —NR¹⁰—SO₂—, —SO₂—NR¹⁰—, —(C₁-C₆)-alkylene, wherein alkylene is    unsubstituted or mono-, di- or trisubstituted independently of one    another by halogen, NH₂ or —OH; or —(C₃-C₆)-cycloalkylene, wherein    cycloalkylene is unsubstituted or mono-, di- or trisubstituted    independently of one another by halogen, —NH₂ or —OH;-   X is a direct bond, a 3- to 7-membered heteroaryl,    —(C₁-C₆)-alkylene, wherein alkylene is unsubstituted or mono-, di-    or trisubstituted independently of one another by halogen, —NH₂ or    —OH; or —(C₃-C₆)-cycloalkylene, wherein cycloalkylene is    unsubstituted or mono-, di- or trisubstituted independently of one    another by halogen, —NH₂ or —OH;    provided that when Q or Q′ is —(C₁-C₆)-alkylene then X is —O—, —S—,    —NR¹⁰—, —C(O)—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—, —S(O)—, —SO₂—, —NR¹⁰—SO₂—    or —SO₂—NR¹⁰—; with the proviso that if X is a direct bond, the    fragment —Q—X—Q′— is not O—O, O—S, S—O, S—S, SO₂—SO₂, SO—SO, SO—SO₂,    SO₂—SO, SO₂—S, S—SO₂, SO—S, S—SO; with the proviso that if X is    oxygen atom or sulphur atom, then Q and Q′ are not oxygen atom or    sulphur atom; and with the further proviso that if X is S(O) or SO₂,    then Q and Q′ are not oxygen atom or sulphur atom;-   W is    -   1. a 5- to 14-membered aryl, wherein aryl is unsubstituted or        mono-, di- or trisubstituted independently of one another by R¹,    -   2. a 5- to 14-membered heteroaryl, wherein heteroaryl is        unsubstituted or mono-, di- or trisubstituted independently of        one another by R¹,    -   3. a 4-to 15 membered mono- or polycyclic group, wherein said        mono- or polycyclic group is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹, or    -   4. a 4-to 15 membered mono- or polycyclic group, containing one,        two, three or four heteroatoms, such as nitrogen, sulphur or        oxygen, wherein said mono- or polycyclic group is unsubstituted        or mono-, di- or trisubstituted independently of one another by        R¹,        provided that if W is a six membered aryl or heteroaryl group,        then Q′ and U are not in an ortho position with respect to each        other;-   R¹ is    -   1. halogen,    -   2. —NO₂,    -   3. —CN,    -   4. —NR⁴R⁵ wherein R⁴ and R⁵, are defined below,    -   5. —O—(C₁-C₈)-alkyl, wherein alkyl is unsubstituted or mono-,        di- or trisubstituted independently of one another by R¹³,    -   6. —OH,    -   7. —SO₂—NH₂,    -   8. (C₁-C₈)-alkyloxy-, wherein alkyl is unsubstituted or mono-,        di- or trisubstituted independently of one another by R¹³,    -   9. (C₆-C₁₄)-aryl, wherein aryl is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹³,    -   10. (C₁-C₈)-alkyl-, wherein alkyl is unsubstituted or mono-, di-        or trisubstituted independently of one another by R¹³,    -   11. hydroxycarbonyl-(C₁-C₈)-alkylureido-, wherein alkyl is        unsubstituted or mono-, di- or trisubstituted independently of        one another by R¹³,    -   12. (C₁-C₈)-alkyloxycarbonyl-(C₁-C₈)-alkylureido-, wherein alkyl        is unsubstituted or mono-, di- or trisubstituted independently        of one another by R¹³,    -   13. (C₁-C₈)-alkylsulfonyl-, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   14. —NH—C(O),    -   15. —NH—C(O)—(C₁-C₈)-alkyl,    -   16. —NH—C(O)—(C₁-C₈)-alkyl,    -   17. —C(O)—NR⁴R⁵, wherein R⁴ and R⁵ are defined below,    -   18. —COOH;    -   19. —C(O)—(C₁-C₆)-alkyl, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   20. —C(O)—O—(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   21. —C(O)—NR¹¹R¹²,    -   22. —C(NH)—NH₂,    -   23. —NH—C(O)—NH₂,    -   24. —S—(C₁-C₈)-alkyl, wherein alkyl is unsubstituted or mono-,        di- or trisubstituted independently of one another by R¹³,    -   25. —(C₁-C₈)-alkylthio, wherein alkyl is unsubstituted or mono-,        di- or trisubstituted independently of one another by R¹³, or    -   26. R¹¹R¹²N—, or    -   two R¹ residues bonded to adjacent ring carbon atoms together        with the carbon atoms to which they are bonded form a dioxalane        ring or an aromatic ring condensed to W, where the ring formed        by the two R¹ residues is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹³,-   R¹¹ and R¹² together with the nitrogen atom to which they are bonded    form a saturated or unsaturated 5- to 6-membered monocyclic    heterocyclic ring which, in addition to the nitrogen atom carrying    R¹¹ and R¹², can contain one or two identical or different ring    heteroatoms chosen from oxygen, sulphur and nitrogen, and in which    one or two of the ring carbon atoms can be substituted by oxygen to    form —C(O)— residue(s),-   R¹³ is halogen, —NO₂, —CN, —OH, —(C₁-C₈)-alkyl, —(C₁-C₈)-alkyloxy,    —CF₃, —C(O)—NH₂, —NH₂ or the residue V—G—M, wherein V, G and M are    as defined below,-   R¹⁰ is hydrogen atom or —(C₁-C₄)-alkyl,-   U and G are independently of one another identical or different and    are a direct bond, —(CH₂)_(m)—, —(CH₂)_(m)—O—(CH₂)_(n)—,    —(CH₂)_(m)—C(O)—NR¹⁰—(CH₂)_(n)—, —(CH₂)—SO₂—(CH₂)_(n)—,    —(CH₂)_(m)—NR¹⁰—C(O)—NR¹⁰—(CH₂)_(n)—,    —(CH₂)_(m)—NR¹⁰—C(O)—(CH₂)_(n)—, —(CH₂)—S—(CH₂)_(n)—,    —(CH₂)_(m)—C(O)—(CH₂)_(n)—, —(CH₂)_(m)—SO₂—NR¹⁰—(CH₂)_(n)—,    —(CH₂)_(m)—NR¹⁰—SO₂—(CH₂)_(n)—, —(CH₂)_(m)—NR¹⁰—SO₂—NR¹⁰—(CH₂)_(n)—,    —(CH₂)_(m)—CH(OH)—(CH₂)_(n)—, —(CH₂)_(m)—O—C(O)—NR¹⁰—(CH₂)_(n)— or    —(CH₂)_(m)—NR¹⁰—C(O)—O—(CH₂)_(n)—,-   n and m are independently of one another identical or different and    are the integers zero, 1, 2, 3, 4, 5 or 6, wherein the alkylene    residues that are formed by —(CH₂)_(m)— or —(CH₂)_(n)— are    unsubstituted or mono-, di- or trisubstituted independently of one    another by —(C₁-C₄)-alkyl; —C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl,    —C(O)—NR⁴R⁵, —SO₂, —NR⁴R⁵ or —(C₁-C₈)-alkylsulfonyl,-   R⁴ and R⁵ are independently of one another identical or different    and are hydrogen atom, —(C₁-C₈)-alkyl, wherein alkyl is    unsubstituted or mono-, di- or tri-substituted independently of one    another by R¹³, —(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl-, wherein alkyl and    aryl independently from one another are unsubstituted or mono-, di-    or trisubstituted by R¹³, —(C₆-C₁₄)-aryl-, wherein aryl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, —(C₆-C₁₄)-heteroaryl, wherein heteroaryl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³ or —(C₆-C₁₄)-heteroaryl-(C₁-C₄)-alkyl-, wherein alkyl    and heteroaryl independently from one another are unsubstituted or    mono-, di- or trisubstituted by R¹³, or-   R⁴ and R⁵ together with the nitrogen atom to which they are bonded    form a saturated 5- to 7-membered monocyclic heterocyclic ring    which, in addition to the nitrogen atom carrying R⁴ and R⁵ can    contain one or two identical or different ring heteroatoms chosen    from oxygen, sulphur and nitrogen; wherein said heterocyclic ring is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³,-   V is    -   1. a direct bond,    -   2. —(C₁-C₆)-alkylene, which is branched or unbranched and which        is unsubstituted or mono-, di- or trisubstituted independently        of one another by halogen, ═O, —CN, —OH, —NR⁴R⁵, —C(O)—OH,        —C(O)—O—(C₁-C₄)-alkyl, —SO₂—NR⁴R⁵, —C(O)—NR⁴R⁵ or        —(C₁-C₈)-alkylsulfonyl,    -   3. a 3- to 7-membered cyclic group, containing up to 1, 2, 3 or        4 heteroatoms chosen from nitrogen, sulphur or oxygen, wherein        said cyclic group is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹⁴,    -   4. a 6- to 14-membered aryl, wherein aryl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹⁴, or    -   5. a heteroaryl, wherein said heteroaryl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹⁴,-   R¹⁴ is R¹, halogen, —OH, —NR⁴R⁵, ═O, —(C₁-C₄)-alkyl,    —(C₁-C₄)-alkoxyl, —NO₂, —C(O)—OH, —CN, —C(O)—O—(C₁-C₄)-alkyl,    —C(O)—NR⁴R⁵, —(C₁-C₈)-alkylsulfonyl, —O-heteroaryl,    —NR¹⁰—C(O)—NH—(C₁-C₈)-alkyl, —NR¹⁰—C(O)—NH—[(C₁-C₈)-alkyl]₂,    —SO₂—NR⁴R⁵, —SR⁴, or —SO₂, wherein R⁴, R⁵ and R¹⁰ are as defined    above, and-   M is    -   1. a hydrogen atom,    -   2. —(C₁-C₈)-alkyl, wherein alkyl is unsubstituted or mono-, di-        or trisubstituted independently of one another by R¹⁴,    -   3. —C(O)—NR⁴R⁵,    -   4. —(C₆-C₁₄)-aryl, wherein aryl is unsubstituted or mono-, di-        or trisubstituted independently of one another by R¹⁴,    -   5. —(C₆-C₁₄)-heteroaryl, wherein heteroaryl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹⁴,    -   6. a 3- to 7-membered cyclic group, wherein said cyclic group is        unsubstituted or mono-, di- or trisubstituted independently of        one another by R¹⁴,    -   7. a 3- to 7-membered cyclic group, containing up to 1, 2, 3 or        4 heteroatoms chosen from nitrogen, sulphur or oxygen, wherein        said cyclic group is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹⁴, wherein R¹⁴        is defined above,    -   8. —NH—CH(NA¹)(NA²), wherein A¹ and A² are independently of one        another identical or different and are a hydrogen atom or        —(C₁-C₈)-alkyl, or A¹ and A² together with the nitrogen atom to        which they are each bonded form a saturated 5- or 6-membered        monocyclic heterocyclic ring, which is saturated or aromatic, or    -   9. —CH(NA¹)(NA²), wherein A¹ and A² are independently of one        another identical or different and are hydrogen atom or        —(C₁-C₈)-alkyl, or A² together with the nitrogen atom to which        it is bonded forms a saturated 5- or 6-membered monocyclic        heterocyclic ring, which contains 2 nitrogen atoms and is        saturated or aromatic,        in all its stereoisomeric forms and mixtures thereof in any        ratio, polymorph forms and mixtures thereof in any ratio and its        physiologically tolerable salts.

In one embodiment, the compounds of formula I are defined as follows:

-   R⁰ is phenyl, wherein phenyl is unsubstituted or mono-, di- or    trisubstituted independently of one another by R²,    -   pyridyl, wherein pyridyl is unsubstituted or mono-, di- or        trisubstituted independently of one another by R²,    -   pyrimidyl, wherein pyrimidyl is unsubstituted or mono-, di- or        trisubstituted independently of one another by R², or    -   naphthyl, wherein naphthyl is unsubstituted or mono-, di- or        trisubstituted independently of one another by R²,-   R² is as defined above and wherein the alkyl- or alkyloxy residue is    unsubstituted or mono-, di- or trisubstituted independently of one    another by an amino residue or a methoxy residue,-   Q and Q′ are as defined above and wherein the alkylene- or    cycloalkylene residue is unsubstituted or mono-, di- or    trisubstituted independently of one another by —NH₂ or —OH;-   X is as defined above,-   W is phenyl, pyridyl, pyrimidyl, benzoxazole, benzthiazole, indole,    benzo[1,3]dioxole, or naphthyl, wherein W is unsubstituted or mono-,    di- or trisubstituted independently of one another by R¹,    provided that if W is a six membered aryl or heteroaryl group, Q′    and U are not in an ortho position with respect to each other;-   R¹, R¹⁰, R¹¹, R¹² and R¹³ are as defined above,-   U and G are independently of one another identical or different and    are a direct bond, —(CH₂)_(m), —(CH₂)_(m)—O—(CH₂)_(n)—,    —(CH₂)_(m)—C(O)—NR¹⁰—(CH₂)_(n), —(CH₂)_(m)—NR¹⁰—C(O)—NR¹⁰—(CH₂)_(n),    —(CH₂)_(m)—NR¹⁰—C(O)—(CH₂)_(n), —(CH₂)_(m)—C(O)—(CH₂)_(n),    —(CH₂)—S—(CH₂)_(n), —(CH₂)_(m)—SO₂—NR¹⁰—(CH₂)_(n),    —(CH₂)_(m)—NR¹⁰—SO₂—(CH₂)_(n), —(CH₂)_(m)—NR¹⁰—SO₂—NR¹⁰—(CH₂)_(n) or    —(CH₂)_(m)—CH(OH)—(CH₂)_(n),    -   wherein n, m, R⁴ and R⁵ are as defined above,        V and M are as defined above,        in all its stereoisomeric forms and mixtures thereof in any        ratio, and its physiologically tolerable salts.

In another embodiment, the compounds of formula I are defined asfollows:

-   R⁰ is phenyl, wherein phenyl is unsubstituted or mono-, di- or    trisubstituted independently of one another by R²,    -   pyridyl, wherein pyridyl is unsubstituted or mono-, di- or        trisubstituted independently of one another by R²,    -   pyrimidyl, wherein pyrimidyl is unsubstituted or mono-, di- or        trisubstituted independently of one another by R², or    -   naphthyl, wherein naphthyl is unsubstituted or mono-, di- or        trisubstituted independently of one another by R²,-   R² is halogen, —CN, —NH₂, —C(O)—NH₂, —(C₁-C₄)-alkyl, or    —(C₁-C₄)-alkyloxy, wherein the alkyl- or alkyloxy residue is    unsubstituted or mono-, di- or trisubstituted independently of one    another by an amino residue or a methoxy residue,-   Q and Q′ are independently of one another identical or different and    are a direct bond, —C(O)—; —O—, —NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,    —SO₂—, —NR¹⁰—SO₂—, —SO₂—NR¹⁰—, —(C₁-C₄)-alkylene, wherein alkylene    is unsubstituted or mono-, di- or trisubstituted independently of    one another by halogen; or —(C₃-C₆)-cycloalkylene, wherein    cycloalkylene is unsubstituted or mono-, di- or trisubstituted    independently of one another by halogen;-   X is a direct bond, —(C₁-C₃)-alkylene, wherein alkylene is    unsubstituted or mono-, di- or trisubstituted independently of one    another by halogen; or —(C₃-C₆)-cycloalkylene, wherein cycloalkylene    is unsubstituted or mono-, di- or trisubstituted independently of    one another by halogen;-   provided that when Q or Q′ is —(C₁-C₃)-alkylene then X is —O—,    —NR¹⁰—, —C(O)—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—, —SO₂—, —NR¹⁰—SO₂— or    —SO₂—NR¹⁰—;-   with the proviso that if X is a direct bond, the fragment —Q—X—Q′—    is not O—O, SO₂—SO₂, or SO—SO₂; and-   with the proviso that if X is oxygen atom, then Q and Q′ are not    oxygen atom or sulphur atom; and-   with the further proviso that if X is SO₂, then Q and Q′ are not    oxygen atom or sulphur atom;-   W is phenyl, pyridyl, pyrimidyl, benzoxazole, benzthiazole, indole,    benzo[1,3]dioxole, or naphthyl, wherein W is unsubstituted or mono-,    di- or trisubstituted independently of one another by R¹,-   provided that if W is a six membered aryl or heteroaryl group, Q′    and U are not in an ortho position with respect to each other;-   R¹ is    -   1. halogen,    -   2. —NO₂,    -   3. —CN,    -   4. —NH₂,    -   5. (C₁-C₆)-alkylamino-, wherein alkyl is unsubstituted or mono-,        di- or trisubstituted independently of one another by R¹³,    -   6. —OH,    -   7. —SO₂—NH₂,    -   8. (C₁-C₆)-alkyloxy-, wherein alkyl is unsubstituted or mono-,        di- or trisubstituted independently of one another by R¹³,    -   9. (C₆-C₁₄)-aryl, wherein aryl is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹³,    -   10 (C₁-C₆)-alkyl-, wherein alkyl is unsubstituted or mono-, di-        or trisubstituted independently of one another by R¹³,    -   11. hydroxycarbonyl-(C₁-C₆)-alkylureido-, wherein alkyl is        unsubstituted or mono-, di- or trisubstituted independently of        one another by R¹³,    -   12. (C₁-C₆)-alkyloxycarbonyl-(C₁-C₆)-alkylureido-, wherein alkyl        is unsubstituted or mono-, di- or trisubstituted independently        of one another by R¹³,    -   13. (C₁-C₆)-alkylsulfonyl-, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   14. bis[(C₁-C₆)-alkyl]amino, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   15. —C(O)—NH₂,    -   16. —C(O)—OH,    -   17. —C(O)—(C₁-C₆)-alkyl, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   18. —C(O)—NH—(C₁-C₆)-alkyl, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   19. —C(O)—NH—[(C₁-C₆)-alkyl]₂, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   20. —C(NH)—NH₂,    -   21. ureido,    -   22. —(C₁-C₆)-alkylthio, wherein alkyl is unsubstituted or mono-,        di- or trisubstituted independently of one another by R¹³, or    -   23. R¹¹R¹²N—, or    -   two R¹ residues bonded to adjacent ring carbon atoms together        with the carbon atoms to which they are bonded form an aromatic        ring condensed to W, where the ring formed by the two R¹        residues is unsubstituted or mono-, di- or trisubstituted        independently of one another by R¹³,-   R¹¹ and R¹² together with the nitrogen atom to which they are bonded    form a saturated or unsaturated 5- to 6-membered monocyclic    heterocyclic ring which, in addition to the nitrogen atom carrying    R¹¹ and R¹² can contain one or two identical or different ring    heteroatoms chosen from oxygen, sulphur and nitrogen, and in which    one or two of the ring carbon atoms can be substituted by oxygen to    form —C(O)— residue(s),-   R¹³ is halogen, —CN, —(C₁-C₆)-alkyl, —(C₁-C₆)-alkyloxy, —CF₃,    —C(O)—NH₂ or —NH₂,-   R¹⁰ is hydrogen atom or —(C₁-C₄)-alkyl,-   U and G are independently of one another identical or different and    are a direct bond, —(CH₂)_(m), —(CH₂)_(m)—O—(CH₂)_(n)—,    —(CH₂)_(m)—C(O)—NR¹⁰—(CH₂)_(n), —(CH₂)_(m)—NR¹⁰—C(O)—NR¹⁰—(CH₂)_(n),    —(CH₂)_(m)—NR¹⁰—C(O)—(CH₂)_(n), —(CH₂)_(m)—C(O)—(CH₂)_(n),    —(CH₂)—S—(CH₂)_(n), —(CH₂)_(m)—SO₂—NR¹⁰—(CH₂)_(n),    —(CH₂)_(m)—NR¹⁰—SO₂—(CH₂)_(n), or    —(CH₂)_(m)—NR¹⁰—SO₂—NR¹⁰—(CH₂)_(n),-   n and m are independently of one another identical or different and    are the integers zero, 1, 2 or 3, wherein the alkylene residues are    unsubstituted or mono-, di- or trisubstituted independently of one    another by —(C₁-C₄)-alkyl; —C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl,    —C(O)—NR⁴R⁵, —SO₂, —NR⁴R⁵ or —(C₁-C₈)-alkylsulfonyl,-   R⁴ and R⁵ are independently of one another identical or different    and are hydrogen atom, —(C₁-C₆)-alkyl, wherein alkyl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, —(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl-, wherein alkyl and    aryl independently from one another are unsubstituted or mono-, di-    or trisubstituted by R¹³, —(C₆-C₁₄)-aryl-, wherein aryl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, —(C₆-C₁₄)-heteroaryl, wherein heteroaryl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³ or —(C₆-C₁₄)-heteroaryl-(C₁-C₄)-alkyl-, wherein alkyl    and heteroaryl independently from one another are unsubstituted or    mono-, di- or trisubstituted by R¹³, or-   R⁴ and R⁵ together with the nitrogen atom to which they are bonded    form a saturated 5- to 7-membered monocyclic heterocyclic ring,    which in addition to the nitrogen atom carrying R⁴ and R⁵ can    contain one or two identical or different ring heteroatoms chosen    from oxygen, sulphur and nitrogen; wherein said heterocyclic ring is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³,-   V is    -   1. a direct bond,    -   2. —(C₁-C₄)-alkylene, which is branched or unbranched and which        is unsubstituted or mono-, di- or trisubstituted independently        of one another by halogen, ═O, —CN, —OH, —NR⁴R⁵, —C(O)—OH,        —C(O)—O—(C₁-C₄)-alkyl, —SO₂, —NR⁴R⁵, —C(O)—NR⁴R⁵ or        —(C₁-C₈)-alkylsulfonyl,    -   3. a 5- to 7-membered cyclic group, containing up to 1, 2, 3 or        4 heteroatoms chosen from nitrogen, sulphur or oxygen, wherein        said cyclic group is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹⁴,    -   4. a 6- to 14-membered aryl, wherein aryl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹⁴, or    -   5. a heteroaryl, wherein said heteroaryl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹⁴,-   R¹⁴ is halogen, —OH, —NR⁴R⁵, ═O, —(C₁-C₄)-alkyl, —(C₁-C₄)-alkoxyl,    —NO₂, —C(O)—OH, —CN, —C(O)—O—(C₁-C₄)-alkyl, —C(O)—NR⁴R⁵,    —(C₁-C₈)-alkylsulfonyl, —C(O)—NR⁴R⁵, —SO₂—NR⁴R⁵,    —C(O)—NH—(C₁-C₈)-alkyl, —C(O)—NH—[(C₁-C₈)-alkyl]₂,    —NR¹⁰—C(O)—NH—(C₁-C₈)-alkyl, —C(O)—NH₂ or    —NR¹⁰—C(O)—NH—[(C₁-C₈)-alkyl]₂, wherein R⁴, R⁵ and R¹⁰ are as    defined above, and-   M is    -   1. a hydrogen atom,    -   2. —(C₁-C₈)-alkyl, wherein alkyl is unsubstituted or mono-, di-        or trisubstituted independently of one another by R¹⁴,    -   3. —C(O)—NR⁴R⁵,    -   4. —(C₆-C₁₄)-aryl, wherein aryl is unsubstituted or mono-, di-        or trisubstituted independently of one another by R¹⁴,    -   5. —(C₆-C₁₄)-heteroaryl, wherein heteroaryl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹⁴,    -   6. a 5- to 7-membered cyclic group, wherein said cyclic group is        unsubstituted or mono-, di- or trisubstituted independently of        one another by R¹⁴, or    -   7. a 5- to 7-membered cyclic group, containing up to 1, 2, 3 or        4 heteroatoms chosen from nitrogen, sulphur or oxygen, wherein        said cyclic group is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹⁴, wherein R¹⁴        is defined above,        in all its stereoisomeric forms and mixtures thereof in any        ratio, and its physiologically tolerable salts.

In yet another embodiment, the compounds of formula I are defined asfollows:

-   R⁰ is phenyl, wherein phenyl is unsubstituted or mono-, di- or    trisubstituted independently of one another by R², or pyridyl,    wherein pyridyl is unsubstituted or mono-, di- or trisubstituted    independently of one another by R²,-   R² is halogen, —CN, —C(O)—NH₂, —(C₁-C₄)-alkyl, or —(C₁-C₄)-alkyloxy,    wherein the alkyl- or alkyloxy residue is unsubstituted or mono-,    di- or trisubstituted independently of one another by an amino    residue or a methoxy residue,-   Q and Q′ are independently of one another identical or different and    are a direct bond, —C(O)—; —O—, —NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,    —SO₂—, —NR¹⁰—SO₂—, —SO₂—NR¹⁰—, or —(C₁-C₄)-alkylene,-   X is a direct bond or —(C₁-C₃)-alkylene, provided that when Q or Q′    is —(C₁-C₃)-alkylene then X is —O—, —NR¹⁰—, —C(O)—, —C(O)—NR¹⁰—,    —NR¹⁰—C(O)—, —SO₂—, —NR¹⁰—SO₂— or —SO₂—NR¹⁰—;    with the proviso that if X is a direct bond, the fragment —Q —X—Q′—    is not O—O or SO₂—SO₂;    and with the proviso that if X is oxygen atom, then Q and Q′ are not    oxygen atom or sulphur atom; and    with the further proviso that if X is SO₂, then Q and Q′ are not    oxygen atom or sulphur atom;-   W is phenyl, pyridyl or pyrimidyl, wherein W is unsubstituted or    mono-, di- or trisubstituted independently of one another by R¹,    provided that Q′ and U are not in an ortho position with respect to    each other;-   R¹ is    -   1. halogen,    -   2. —NO₂,    -   3. —CN,    -   4. —NH₂,    -   5. (C₁-C₄)-alkylamino-, wherein alkyl is unsubstituted or mono-,        di- or trisubstituted independently of one another by R¹³,    -   6. —OH,    -   7. —SO₂—NH₂,    -   8. (C₁-C₄)-alkyloxy-, wherein alkyl is unsubstituted or mono-,        di- or trisubstituted independently of one another by R¹³,    -   9. (C₆-C₁₄)-aryl, wherein aryl is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹³,    -   10 (C₁-C₄)-alkyl-, wherein alkyl is unsubstituted or mono-, di-        or trisubstituted independently of one another by R¹³,    -   11. hydroxycarbonyl-(C₁-C₄)-alkylureido-, wherein alkyl is        unsubstituted or mono-, di- or trisubstituted independently of        one another by R¹³,    -   12. (C₁-C₄)-alkyloxycarbonyl-(C₁-C₄)-alkylureido-, wherein alkyl        is unsubstituted or mono-, di- or trisubstituted independently        of one another by R¹³,    -   13. (C₁-C₄)-alkylsulfonyl-, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   14. bis[(C₁-C₄)-alkyl]amino, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   15. —C(O)—NH₂,    -   16. —C(O)—OH,    -   17. —C(O)—(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   18. —C(O)—NH—(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   19. —C(O)—NH—[(C₁-C₄)-alkyl]₂, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   20. —C(NH)—NH₂,    -   21. ureido,    -   22. —(C₁-C₄)-alkylthio, wherein alkylthio is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³, or    -   23. R¹¹R¹²N—, or    -   two R¹ residues bonded to adjacent ring carbon atoms together        with the carbon atoms to which they are bonded form an aromatic        ring condensed to W, where the ring formed by the two R¹        residues is unsubstituted or mono-, di- or trisubstituted        independently of one another by R¹³,-   R¹¹ and R¹² together with the nitrogen atom to which they are bonded    form a saturated or unsaturated 5- to 6-membered monocyclic    heterocyclic ring which, in addition to the nitrogen atom carrying    R¹¹ and R¹², can contain one or two identical or different ring    heteroatoms chosen from oxygen, sulphur and nitrogen,-   R¹³ is halogen, —CN, —(C₁-C₄)-alkyl, —(C₁-C₄)-alkyloxy, —CF₃,    —C(O)—NH₂ or —NH₂,-   R¹⁰ is hydrogen atom or —(C₁-C₄)-alkyl,-   U and G are independently of one another identical or different and    are a direct bond,    -   —(CH₂)_(m), —(CH₂)_(m)—C(O)—NR¹⁰—(CH₂)_(n),        —(CH₂)_(m)—NR¹⁰—C(O)—NR¹⁰—(CH₂)_(n),        —(CH₂)_(m)—NR¹⁰—C(O)—(CH₂)_(n), —(CH₂)_(m)—C(O)—(CH₂)_(n),        —(CH₂)_(m)—SO₂—NR¹⁰—(CH₂)_(n), or —(CH₂)_(m)—NR¹⁰—SO₂—(CH₂)_(n),-   n and m are are independently of one another identical or different    and are the integers zero, 1, 2 or 3, wherein the alkylene residues    are unsubstituted or mono-, di- or trisubstituted independently of    one another by —(C₁-C₄)-alkyl; —C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl or    —C(O)—NR⁴R⁵,-   R⁴ and R⁵ are independently of one another identical or different    and are hydrogen atom, —(C₁-C₆)-alkyl, wherein alkyl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, —(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl-, wherein alkyl and    aryl independently from one another are unsubstituted or mono-, di-    or trisubstituted by R¹³, —(C₆-C₁₄)-aryl-, wherein aryl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, —(C₆-C₁₄)-heteroaryl, wherein heteroaryl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³ or —(C₆-C₁₄)-heteroaryl-(C₁-C₄)-alkyl-, wherein alkyl    and heteroaryl independently from one another are unsubstituted or    mono-, di- or trisubstituted by R¹³, or-   R⁴ and R⁵ together with the nitrogen atom to which they are bonded    form a saturated 5- to 7-membered monocyclic heterocyclic ring    which, in addition to the nitrogen atom carrying R⁴ and R⁵ can    contain one or two identical or different ring heteroatoms chosen    from oxygen, sulphur and nitrogen; wherein said heterocyclic ring is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³,-   V is    -   1. a direct bond,    -   2. —(C₁-C₄)-alkylene, which is branched or unbranched and which        is unsubstituted or mono-, di- or trisubstituted independently        of one another by halogen, ═O, —CN, —OH, —NR⁴R⁵, —C(O)—OH,        —C(O)—O—(C₁-C₄)-alkyl, —SO₂—NR⁴R⁵, —C(O)—NR⁴R⁵ or        —(C₁-C₄)-alkylsulfonyl,    -   3. a 5- to 7-membered cyclic group, containing up to 1, 2, 3 or        4 heteroatoms chosen from nitrogen, sulphur or oxygen, wherein        said cyclic group is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹⁴,    -   4. a 6- to 14-membered aryl, wherein aryl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹⁴, or    -   5. a 6- to 14-membered heteroaryl, wherein said heteroaryl is        unsubstituted or mono-, di- or trisubstituted independently of        one another by R¹⁴,-   R¹⁴ is halogen, —OH, —NR⁴R⁵, ═O, —(C₁-C₄)-alkyl, —(C₁-C₄)-alkoxyl,    —NO₂, —C(O)—OH, —CN, —C(O)—O—(C₁-C₄)-alkyl, —C(O)—NR⁴R⁵,    —(C₁-C₈)-alkylsulfonyl, —C(O)—NR⁴R⁵, —SO₂—NR⁴R⁵,    —C(O)—NH—(C₁-C₈)-alkyl, —C(O)—NH—[(C₁-C₈)-alkyl]₂,    —NR¹⁰—C(O)—NH—(C₁-C₈)-alkyl, —C(O)—NH₂ or    —NR¹⁰—C(O)—NH—[(C₁-C₈)-alkyl]₂, wherein R⁴, R⁵ and R¹⁰ are as    defined above, and-   M is    -   1. a hydrogen atom,    -   2. —(C₁-C₈)-alkyl, wherein alkyl is unsubstituted or mono-, di-        or trisubstituted independently of one another by R¹⁴,    -   3. —C(O)—NR⁴R⁵,    -   4. —(C₆-C₁₄)-aryl, wherein aryl is unsubstituted or mono-, di-        or trisubstituted independently of one another by R¹⁴,    -   5. —(C₆-C₁₄)-heteroaryl, wherein heteroaryl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹⁴,    -   6. a 5- to 7-membered cyclic group, wherein said cyclic group is        unsubstituted or mono-, di- or trisubstituted independently of        one another by R¹⁴, or    -   7. a 5- to 7-membered cyclic group, containing up to 1, 2, 3 or        4 heteroatoms chosen from nitrogen, sulphur or oxygen, wherein        said cyclic group is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹⁴, wherein R¹⁴        is defined above,        in all its stereoisomeric forms and mixtures thereof in any        ratio, and its physiologically tolerable salts.

In another embodiment, the compounds of formula I are defined asfollows:

-   R⁰ is phenyl, wherein phenyl is unsubstituted or mono- or    disubstituted independently of one another by R², or    -   pyridyl, wherein pyridyl is unsubstituted or mono-,        disubstituted independently of one another by R²,-   R² is halogen, —CN, —C(O)—NH₂, —(C₁-C₃)-alkyl, or —(C₁-C₃)-alkyloxy,    wherein the alkyl- or alkyloxy residue is unsubstituted or mono-,    di- or trisubstituted independently of one another by an amino    residue or a methoxy residue,-   Q and Q′ are independently of one another identical or different and    are a direct bond, —C(O)—; —O—, —NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,    —SO₂—, —NR¹⁰—SO₂—, —SO₂—NR¹⁰—, or —(C₁-C₄)-alkylene,-   X is a direct bond or —(C₁-C₃)-alkylene,-   provided that when Q or Q′ is —(C₁-C₃)-alkylene then X is —O—,    —NR¹⁰—, —C(O)—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—, —SO₂—, —NR¹⁰—SO₂— or    —SO₂—NR¹⁰—;    with the proviso that if X is a direct bond, the fragment —Q—X—Q′—    is not O—O or SO₂—SO₂;    and with the proviso that if X is oxygen atom, then Q and Q′ are not    oxygen atom or sulphur atom; and    with the further proviso that if X is SO₂, then Q and Q′ are not    oxygen atom or sulphur atom;-   W is phenyl, pyridyl or pyrimidyl, wherein W is unsubstituted or    mono-, di- or trisubstituted independently of one another by R¹,    provided that Q′ and U are not in an ortho position with respect to    each other;-   R¹ is    -   1. halogen,    -   2. —NO₂,    -   3. —CN,    -   4. —NH₂,    -   5. (C₁-C₄)-alkylamino-, wherein alkyl is unsubstituted or mono-,        di- or trisubstituted independently of one another by R¹³,    -   6. —OH,    -   7. —SO₂—NH₂,    -   8. (C₁-C₄)-alkyloxy-, wherein alkyl is unsubstituted or mono-,        di- or trisubstituted independently of one another by R¹³,    -   9. (C₆-C₁₄)-aryl, wherein aryl is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹³,    -   10. (C₁-C₄)-alkyl-, wherein alkyl is unsubstituted or mono-, di-        or trisubstituted independently of one another by R¹³,    -   11. (C₁-C₄)-alkylsulfonyl-, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   12. bis[(C₁-C₄)-alkyl]amino, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   13. —C(O)—NH₂,    -   14. —C(O)—OH,    -   15. —C(O)—(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   16. —C(O)—NH—(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   17. —C(O)—NH—[(C₁-C₄)-alkyl]₂, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   18. —C(NH)—NH₂,    -   19. ureido,    -   20. —(C₁-C₄)-alkylthio, wherein alkylthio is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³, or    -   21. R¹¹R¹²N—, or    -   two R¹ residues bonded to adjacent ring carbon atoms together        with the carbon atoms to which they are bonded form an aromatic        ring condensed to W, where the ring formed by the two R¹        residues is unsubstituted or mono-, di- or trisubstituted        independently of one another by R¹³,-   R¹¹ and R¹² together with the nitrogen atom to which they are bonded    form a saturated or unsaturated 5- to 6-membered monocyclic    heterocyclic ring which, in addition to the nitrogen atom carrying    R¹¹ and R¹², can contain one or two identical or different ring    heteroatoms chosen from oxygen or nitrogen,-   R¹³ is halogen, —CN, —(C₁-C₄)-alkyl, —(C₁-C₄)-alkyloxy, —CF₃,    —C(O)—NH₂ or —NH₂,-   R¹⁰ is hydrogen atom or —(C₁-C₄)-alkyl,-   U is a direct bond, —(CH₂)_(m), —(CH₂)_(m)—C(O)—NR¹⁰—(CH₂)_(n),    —(CH₂)_(m)—NR¹⁰—C(O)—(CH₂)_(n), —(CH₂)_(m)—C(O)—(CH₂)_(n),    —(CH₂)_(m)—SO₂—NR¹⁰—(CH₂)_(n), or —(CH₂)_(m)—NR¹⁰—SO₂—(CH₂)_(n),-   n and m are independently of one another identical or different and    are the integers zero, 1, 2 or 3, wherein the alkylene residues are    unsubstituted or mono-, di- or trisubstituted independently of one    another by —(C₁-C₄)-alkyl; —C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl or    —C(O)—NR⁴R⁵,-   R⁴ and R⁵ are independently of one another identical or different    and are hydrogen atom, —(C₁-C₆)-alkyl, wherein alkyl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, —(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl-, wherein alkyl and    aryl independently from one another are unsubstituted or mono-, di-    or trisubstituted by R¹³, —(C₆-C₁₄)-aryl-, wherein aryl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, —(C₆-C₁₄)-heteroaryl, wherein heteroaryl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³ or —(C₆-C₁₄)-heteroaryl-(C₁-C₄)-alkyl-, wherein alkyl    and heteroaryl independently from one another are unsubstituted or    mono-, di- or trisubstituted by R¹³, or-   R⁴ and R⁵ together with the nitrogen atom to which they are bonded    form a saturated 5- to 7-membered monocyclic heterocyclic ring    which, in addition to the nitrogen atom carrying R⁴ and R⁵, can    contain one or two identical or different ring heteroatoms chosen    from oxygen, sulphur and nitrogen; wherein said heterocyclic ring is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³,-   G is a direct bond, —(CH₂)_(m), —(CH₂)_(m)—O—(CH₂)_(n—),    —(CH₂)_(m)—C(O)—NR¹⁰—(CH₂)_(n), —(CH₂)_(m)—NR¹⁰—C(O)—NR¹⁰—(CH₂)_(n),    —(CH₂)_(m)—NR¹⁰—C(O)—(CH₂)_(n), —(CH₂)_(m)—C(O)—(CH₂)_(n),    —(CH₂)—S—(CH₂)_(n), —(CH₂)_(m)—SO₂—NR¹⁰—(CH₂)_(n),    —(CH₂)_(m)—NR¹⁰—SO₂—(CH₂)_(n), —(CH₂)_(m)—NR¹⁰—SO₂—NR¹⁰—(CH₂)_(n) or    —(CH₂)_(m)—SO₂—(CH₂)_(n),-   wherein n, m, and R¹⁰ are as defined above-   V is    -   1. a direct bond,    -   2. —(C₁-C₄)-alkylene, which is branched or unbranched and which        is unsubstituted or mono-, di- or trisubstituted independently        of one another by halogen, ═O, —CN, —NR⁴R⁵, —C(O)—OH,        —C(O)—O—(C₁-C₄)-alkyl, —SO₂—NR⁴R⁵, —C(O)—NR⁴R⁵ or        —(C₁-C₄)-alkylsulfonyl,    -   3. a 5- to 7-membered cyclic group, containing up to 1, 2, 3 or        4 heteroatoms chosen from nitrogen, sulphur or oxygen, wherein        said cyclic group is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹⁴,    -   4. a 6- to 14-membered aryl, wherein aryl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹⁴, or    -   5. a 6- to 14-membered heteroaryl, wherein said heteroaryl is        unsubstituted or mono-, di- or trisubstituted independently of        one another by R¹⁴,-   R¹⁴ is halogen, —OH, —NR⁴R⁵, ═O, —(C₁-C₄)-alkyl, —(C₁-C₄)-alkoxyl,    —NO₂, —C(O)—OH, —CN, —C(O)—O—(C₁-C₄)-alkyl, —C(O)—NR⁴R⁵,    —(C₁-C₈)-alkylsulfonyl, —C(O)—NR⁴R⁵, —SO₂—NR⁴R⁵,    —C(O)—NH—(C₁-C₈)-alkyl, —C(O)—NH—[(C₁-C₈)-alkyl]₂,    —NR¹⁰—C(O)—NH—(C₁-C₈)-alkyl, —C(O)—NH₂ or    —NR¹⁰—C(O)—NH—[(C₁-C8)-alkyl]₂, wherein R⁴, R⁵ and R¹⁰ are as    defined above, and-   M is    -   1. a hydrogen atom,    -   2. —(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or mono-, di-        or trisubstituted independently of one another by R¹⁴,    -   3. —C(O)—NR⁴R⁵,    -   4. —(C₆-C₁₄)-aryl, wherein aryl is unsubstituted or mono-, di-        or trisubstituted independently of one another by R¹⁴,    -   5. —(C₆-C₁₄)-heteroaryl, wherein heteroaryl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹⁴,    -   6. a 5- to 7-membered cyclic group, wherein said cyclic group is        unsubstituted or mono-, di- or trisubstituted independently of        one another by R¹⁴, or    -   7. a 5- to 7-membered cyclic group, containing up to 1, 2, 3 or        4 heteroatoms chosen from nitrogen, sulphur or oxygen, wherein        said cyclic group is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹⁴, wherein R¹⁴        is defined above,        in all its stereoisomeric forms and mixtures thereof in any        ratio, and its physiologically tolerable salts.

In another embodiment, compounds of formula I are defined as follows:

-   R⁰ is phenyl, wherein phenyl is unsubstituted or mono- or    disubstituted independently of one another by R², or    -   pyridyl, wherein pyridyl is unsubstituted or mono-,        disubstituted independently of one another by R²,-   R² is halogen, —CN, —C(O)—NH₂, —(C₁-C₃)-alkyl, or —(C₁-C₃)-alkyloxy,    wherein the alkyl- or alkyloxy residue is unsubstituted or mono-,    di- or trisubstituted independently of one another by an amino    residue or a methoxy residue,-   Q and Q′ are independently of one another identical or different and    are a direct bond, —C(O)—; —O—, —NR¹⁰—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—,    —SO₂—, —NR¹⁰—SO₂—, —SO₂—NR¹⁰—, or —(C₁-C₄)-alkylene,-   X is a direct bond or —(C₁-C₃)-alkylene,-   provided that when Q or Q′ is —(C₁-C₃)-alkylene then X is —O—,    —NR¹⁰—, —C(O)—, —C(O)—NR¹⁰—, —NR¹⁰—C(O)—, —SO₂—, —NR¹⁰—SO₂— or    —SO₂—NR¹⁰—;    with the proviso that if X is a direct bond, the fragment —Q—X—Q′—    is not O—O or SO₂—SO₂;    and with the proviso that if X is oxygen atom, then Q and Q′ are not    oxygen atom or sulphur atom; and    with the further proviso that if X is SO₂, then Q and Q′ are not    oxygen atom or sulphur atom;-   W is phenyl or pyridyl, wherein W is unsubstituted or mono-, di- or    trisubstituted independently of one another by R¹,    provided that Q′ and U are not in an ortho position with respect to    each other;-   R¹ is    -   1. halogen,    -   2. —NO₂,    -   3. —CN,    -   4. —NH₂,    -   5. (C₁-C₄)-alkylamino-, wherein alkyl is unsubstituted or mono-,        di- or trisubstituted independently of one another by R¹³,    -   6. —OH,    -   7. —SO₂—NH₂,    -   8. (C₁-C₄)-alkyloxy-, wherein alkyl is unsubstituted or mono-,        di- or trisubstituted independently of one another by R¹³,    -   9. (C₆-C₁₄)-aryl, wherein aryl is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹³,    -   10. (C₁-C₄)-alkyl-, wherein alkyl is unsubstituted or mono-, di-        or trisubstituted independently of one another by R¹³,    -   11. (C₁-C₄)-alkylsulfonyl-, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   12. bis[(C₁-C₄)-alkyl]amino, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   13. —C(O)—NH₂,    -   14. —C(O)—OH,    -   15. —C(O)—(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   16. —C(O)—NH—(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   17. —C(O)—NH—[(C₁-C₄)-alkyl]₂, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   18. —C(NH)—NH₂,    -   19. ureido,    -   20. —(C₁-C₄)-alkylthio, wherein alkylthio is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³, or    -   21. R¹¹R¹²N—, or    -   two R¹ residues bonded to adjacent ring carbon atoms together        with the carbon atoms to which they are bonded form an aromatic        ring condensed to W, where the ring formed by the two R¹        residues is unsubstituted or mono-, di- or trisubstituted        independently of one another by R¹³,    -   R¹¹ and R¹² together with the nitrogen atom to which they are        bonded form a saturated or unsaturated 5- to 6-membered        monocyclic heterocyclic ring which, in addition to the nitrogen        atom carrying R¹¹ and R¹², can contain one or two identical or        different ring heteroatoms chosen from oxygen or nitrogen,-   R¹³ is halogen, —CN, —(C₁-C₄)-alkyl, —(C₁-C₄)-alkyloxy, —CF₃,    —C(O)—NH₂ or —NH₂,-   R¹⁰ is hydrogen atom or —(C₁-C₄)-alkyl,-   U is a direct bond, —(CH₂)_(m), —(CH₂)_(m)—C(O)—NR¹⁰—(CH₂)_(n),    —(CH₂)_(m)—NR¹⁰—C(O)—(CH₂)_(n), —(CH₂)_(m)—C(O)—(CH₂)_(n),    —(CH₂)_(m)—SO₂—NR¹⁰—(CH₂)_(n), or —(CH₂)_(m)—NR¹⁰—SO₂—(CH₂)_(n),-   n and m are are independently of one another identical or different    and are the integers zero, 1, 2 or 3, wherein the alkylene residues    are unsubstituted or mono-, di- or trisubstituted independently of    one another by —(C₁-C₄)-alkyl; —C(O)—OH, —C(O)—O—(C₁-C₄)-alkyl or    —C(O)—NR⁴R⁵,-   R⁴ and R⁵ are independently of one another identical or different    and are hydrogen atom, —(C₁-C₆)-alkyl, wherein alkyl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, —(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl-, wherein alkyl and    aryl independently from one another are unsubstituted or mono-, di-    or trisubstituted by R¹³, —(C₆-C₁₄)-aryl-, wherein aryl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, —(C₆-C₁₄)-heteroaryl, wherein heteroaryl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³ or —(C₆-C₁₄)-heteroaryl-(C₁-C₄)-alkyl-, wherein alkyl    and heteroaryl independently from one another are unsubstituted or    mono-, di- or trisubstituted by R¹³, or-   R⁴ and R⁵ together with the nitrogen atom to which they are bonded    form a saturated 5- to 7-membered monocyclic heterocyclic ring    which, in addition to the nitrogen atom carrying R⁴ and R⁵, can    contain one or two identical or different ring heteroatoms chosen    from oxygen, sulphur and nitrogen; wherein said heterocyclic ring is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³,-   G is a direct bond, —(CH₂)_(m), —(CH₂)_(m)—O—(CH₂)_(n)—,    —(CH₂)_(m)—C(O)—NR¹⁰—(CH₂)_(n), —(CH₂)_(m)—NR¹⁰—C(O)—NR¹⁰—(CH₂)_(n),    —(CH₂)_(m)—NR¹⁰—C(O)—(CH₂)_(n), —(CH₂)_(m)—C(O)—(CH₂)_(n),    —(CH₂)—S—(CH₂)_(n), —(CH₂)_(m)—SO₂—NR¹⁰—(CH₂)_(n),    —(CH₂)_(m)—NR¹⁰—SO₂—(CH₂)_(n), —(CH₂)_(m)—NR¹⁰—SO₂—NR¹⁰—(CH₂)_(n) or    —(CH₂)_(m)—SO₂—(CH₂)_(n),    -   wherein n, m, and R¹⁰ are as defined above-   V is    -   1. a direct bond,    -   2. —(C₁-C₄)-alkylene, which is branched or unbranched and which        is unsubstituted or mono-, di- or trisubstituted independently        of one another by halogen, ═O, —CN, —NR⁴R⁵, —C(O)—OH,        —C(O)—O—(C₁-C₄)-alkyl, —SO₂—NR⁴R⁵, —C(O)—NR⁴R⁵ or        —(C₁-C₄)-alkylsulfonyl,    -   3. a 5- to 7-membered cyclic group, containing up to 1, 2, 3 or        4 heteroatoms chosen from nitrogen, sulphur or oxygen, wherein        said cyclic group is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹⁴,    -   4. a 6- to 14-membered aryl, wherein aryl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹⁴, or    -   5. a 6- to 14-membered heteroaryl, wherein said heteroaryl is        unsubstituted or mono-, di- or trisubstituted independently of        one another by R¹⁴,-   R¹⁴ is halogen, —OH, —NR⁴R⁵, ═O, —(C₁-C₄)-alkyl, —(C₁-C₄)-alkoxyl,    —NO₂, —C(O)—OH, —CN, —C(O)—O—(C₁-C₄)-alkyl, —C(O)—NR⁴R⁵,    —(C₁-C₈)-alkylsulfonyl, —C(O)—NR⁴R⁵, —SO₂—NR⁴R⁵,    —C(O)—NH—(C₁-C₈)-alkyl, —C(O)—NH—[(C₁-C₈)-alkyl]₂,    —NR¹⁰—C(O)—NH—(C₁-C₈)-alkyl, —C(O)—NH₂ or    —NR¹⁰—C(O)—NH—[(C₁-C₈)-alkyl]₂, wherein R⁴, R⁵ and R¹⁰ are as    defined above, and-   M is    -   1. a hydrogen atom,    -   2. —(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or mono-, di-        or trisubstituted independently of one another by R¹⁴,    -   3. —C(O)—NR⁴R⁵,    -   4. —(C₆-C₁₄)-aryl, wherein aryl is unsubstituted or mono-, di-        or trisubstituted independently of one another by R¹⁴,    -   5. —(C₆-C₁₄)-heteroaryl, wherein heteroaryl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹⁴,    -   6. a 5- to 7-membered cyclic group, wherein said cyclic group is        unsubstituted or mono-, di- or trisubstituted independently of        one another by R¹⁴, or    -   7. a 5- to 7-membered cyclic group, containing up to 1, 2, 3 or        4 heteroatoms chosen from nitrogen, sulphur or oxygen, wherein        said cyclic group is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹⁴, wherein R¹⁴        is defined above,        in all its stereoisomeric forms and mixtures thereof in any        ratio, and its physiologically tolerable salts.

In another embodiment, compounds of formula I are defined as follows:

-   R⁰ is —(C₆-C₁₄)-aryl, wherein aryl is chosen from the group phenyl,    naphthyl, biphenylyl, fluorenyl and anthracenyl and is unsubstituted    or mono- or disubstituted independently of one another by R², or    -   —(C₆-C₁₄)-heteroaryl, wherein heteroaryl is chosen from the        group aziridine, oxirane, azetidine, pyrrole, furan, thiophene,        dioxole, imidazole, pyrazole, oxazole, isoxazole, thiazole,        isothiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole,        pyridine, pyran, thiopyran, pyridazine, pyrimidine, pyrazine,        1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine,        1,3-thiazine, 1,4-thiazine, 1,2,3-triazine, 1,2,4-triazine,        1,3,5-triazine, azepine, 1,2-diazepine, 1,3-diazepine,        1,4-diazepine, indole, isoindole, benzofuran, benzothiophene,        1,3-benzodioxole, indazole, chromane, benzimidazole,        benzoxazole, benzothiazole, quinoline, isoquinoline,        isochromane, cinnoline, quinazoline, quinoxaline, phthalazine,        pteridine pyridyl, pyridopyridines, pyridoimidazoles,        pyridopyrimidines and purine and is unsubstituted or mono- or        disubstituted independently of one another by R₂,-   R² is halogen, —CN, —C(O)—NH₂, —(C₁-C₃)-alkyl, or —(C₁-C₃)-alkyloxy,    wherein the alkyl- or alkyloxy residue is unsubstituted or mono-,    di- or trisubstituted independently of one another by an amino    residue or a methoxy residue,-   Q is a direct bond,-   Q′ is —O—-   X is —(C₁-C₃)-alkylene,-   W is —(C₆-C₁₄)-aryl, wherein aryl is chosen from the group phenyl,    naphthyl, biphenylyl, fluorenyl and anthracenyl, or    -   —(C₆-C₁₄)-heteroaryl, wherein heteroaryl is chosen from the        group aziridine, oxirane, azetidine, pyrrole, furan, thiophene,        dioxole, imidazole, pyrazole, oxazole, isoxazole, thiazole,        isothiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole,        pyridine, pyran, thiopyran, pyridazine, pyrimidine, pyrazine,        1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine,        1,3-thiazine, 1,4-thiazine, 1,2,3-triazine, 1,2,4-triazine,        1,3,5-triazine, azepine, 1,2-diazepine, 1,3-diazepine,        1,4-diazepine, indole, isoindole, benzofuran, benzothiophene,        1,3-benzodioxole, indazole, chromane, benzimidazole,        benzoxazole, benzothiazole, quinoline, isoquinoline,        isochromane, cinnoline, quinazoline, quinoxaline, phthalazine,        pteridine pyridyl, pyridopyridines, pyridoimidazoles,        pyridopyrimidines and purine,    -   wherein W is unsubstituted or mono-, di- or trisubstituted        independently of one another by R¹,        provided that Q′ and U are in a 1,2- or 1,3- substitution        relationship with respect to each other; and further provided        that if Q′ and U are in a 1,3- substitution relationship, the 2        position is unsubstituted;-   R¹ is    -   1. halogen,    -   2. —NO₂,    -   3. —CN,    -   4. —NH₂,    -   5. (C₁-C₄)-alkylamino-, wherein alkyl is unsubstituted or mono-,        di- or trisubstituted independently of one another by R¹³,    -   6. —OH,    -   7. —SO₂—NH₂,    -   8. (C₁-C₄)-alkyloxy-, wherein alkyl is unsubstituted or mono-,        di- or trisubstituted independently of one another by R¹³,    -   9. (C₆-C₁₄)-aryl, wherein aryl is chosen from the group phenyl,        naphthyl, biphenylyl, fluorenyl and anthracenyl, and is        unsubstituted or mono-, di- or trisubstituted independently of        one another by R¹³,    -   10. (C₁-C₄)-alkyl-, wherein alkyl is unsubstituted or mono-, di-        or trisubstituted independently of one another by R¹³,    -   11. (C₁-C₄)-alkylsulfonyl-, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   12. bis[(C₁-C₄)-alkyl]amino, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   13. —C(O)—NH₂,    -   14. —C(O)—OH,    -   15. —C(O)—(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   16. —C(O)—NH—(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   17. —C(O)—NH—[(C₁-C₄)-alkyl]₂, wherein alkyl is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³,    -   18. —C(NH)—NH₂,    -   19. ureido,    -   20. —(C₁-C₄)-alkylthio, wherein alkylthio is unsubstituted or        mono-, di- or trisubstituted independently of one another by        R¹³, or    -   21. R¹¹R¹²N—,-   R¹¹ and R¹² together with the nitrogen atom to which they are bonded    form a residue chosen from the group piperidine, morpholine,    piperazine, thiomorpholine, pyrrolidine, pyrrolidinone, and    ketopiperazine;-   R¹³ is halogen, —CN, —(C₁-C₄)-alkyl, —(C₁-C₄)-alkyloxy, —CF₃,    —C(O)—NH₂ or —NH₂,-   R¹⁰ is hydrogen atom or —(C₁-C₄)-alkyl,-   U is —(CH₂)_(m)—C(O)—NR¹⁰—(CH₂)_(n), wherein n and m are    independently of one another identical or different and are the    integers zero, 1 or 2,-   R⁴ and R⁵ are independently of one another identical or different    and are hydrogen atom, —(C₁-C₆)-alkyl, wherein alkyl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, —(C₆-C₁₄)-aryl-(C₁-C₄)-alkyl-, wherein aryl is as    defined for W and alkyl and aryl independently from one another are    unsubstituted or mono-, di- or trisubstituted by R¹³,    —(C₆-C₁₄)-aryl-, wherein aryl is as defined for W and is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, —(C₆-C₁₄)-heteroaryl, wherein heteroaryl is as    defined for W and is unsubstituted or mono-, di- or trisubstituted    independently of one another by R¹³ or    —(C₆-C₁₄)-heteroaryl-(C₁-C₄)-alkyl-, wherein heteroaryl is as    defined for W and alkyl and heteroaryl independently from one    another are unsubstituted or mono-, di- or trisubstituted by R¹³, or-   R⁴ and R⁵ together with the nitrogen atom to which they are bonded    form a residue chosen from the group aziridine, oxirane, azetidine,    pyrrole, furan, thiophene, dioxole, imidazole, pyrazole, oxazole,    isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole,    tetrazole, pyridine, pyran, thiopyran, pyridazine, pyrimidine,    pyrazine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine,    1,3-thiazine, 1,4-thiazine, 1,2,3-triazine, 1,2,4-triazine,    1,3,5-triazine, azepine, 1,2-diazepine, 1,3-diazepine, and    1,4-diazepine, wherein said residue is unsubstituted or mono-, di-    or trisubstituted independently of one another by R¹³,-   G is a direct bond, —(CH₂)_(m), —(CH₂)_(m)—O—(CH₂)_(n)—,    —(CH₂)_(m)—C(O)—NR¹⁰—(CH₂)_(n), —(CH₂)_(m)—NR¹⁰—C(O)—NR¹⁰—(CH₂)_(n),    —(CH₂)_(m)—NR¹⁰—C(O)—(CH₂)_(n), —(CH₂)_(m)—C(O)—(CH₂)_(n),    —(CH₂)_(m)—SO₂—NR¹⁰—(CH₂)_(n), —(CH₂)_(m)—NR¹⁰—SO₂—(CH₂)_(n),    —(CH₂)_(m)—SO₂—(CH₂)_(n) or —(CH₂)_(m)—NR¹⁰—SO₂—NR¹⁰—(CH₂)_(n),    -   wherein n, m, and R¹⁰ are as defined above    -   V is    -   1. a 5- to 7-membered cyclic group chosen from the group        pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene,        dihydropyridine, tetrahydropyridine, piperidine, 1,3-dioxolane,        2-imidazoline, imidazolidine, 4,5-dihydro-1,3-oxazol,        1,3-oxazolidine, 4,5-dihydro-1,3-thiazole, 1,3-thiazolidine,        perhydro-1,4-dioxane, piperazine, perhydro-1,4-oxazine        (morpholine), perhydro-1,4-thiazine (thiomorpholine),        perhydroazepine, indoline, isoindoline,        1,2,3,4-tetrahydroquinoline, and 1,2,3,4-tetrahydroisoquinoline,        wherein said cyclic group is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹⁴,    -   2. —(C₆-C₁₄)-aryl, wherein aryl is chosen from the group phenyl,        naphthyl, biphenylyl, fluorenyl and anthracenyl and is        unsubstituted or mono-, di- or trisubstituted independently of        one another by R¹⁴, or    -   3. —(C₆-C₁₄)-heteroaryl, wherein heteroaryl is chosen from the        group aziridine, oxirane, azetidine, pyrrole, furan, thiophene,        dioxole, imidazole, pyrazole, oxazole, isoxazole, thiazole,        isothiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole,        pyridine, pyran, thiopyran, pyridazine, pyrimidine, pyrazine,        1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine,        1,3-thiazine, 1,4-thiazine, 1,2,3-triazine, 1,2,4-triazine,        1,3,5-triazine, azepine, 1,2-diazepine, 1,3-diazepine,        1,4-diazepine, indole, isoindole, benzofuran, benzothiophene,        1,3-benzodioxole, indazole, chromane, benzimidazole,        benzoxazole, benzothiazole, quinoline, isoquinoline,        isochromane, cinnoline, quinazoline, quinoxaline, phthalazine,        pteridine pyridyl, pyridopyridines, pyridoimidazoles,        pyridopyrimidines and purine, wherein said heteroaryl is        unsubstituted or mono-, di- or trisubstituted independently of        one another by R¹⁴,-   R¹⁴ is halogen, —OH, —NR⁴R⁵, ═O, —(C₁-C₄)-alkyl, —(C₁-C₄)-alkoxyl,    —NO₂, —C(O)—OH, —CN, —C(O)—O—(C₁-C₄)-alkyl, —C(O)—NR⁴R⁵,    —(C₁-C₈)-alkylsulfonyl, —C(O)—NH₂, —SO₂—NR⁴R⁵,    —C(O)—NH—(C₁-C₈)-alkyl, —C(O)—NH—[(C₁-C₈)-alkyl]₂,    —NR¹⁰—C(O)—NH—(C₁-C₈)-alkyl, —C(O)—NH₂ or    —NR¹⁰—C(O)—NH—[(C₁-C₈)-alkyl]₂, wherein R⁴, R⁵ and R¹⁰ are as    defined above, and-   M is    -   1. a hydrogen atom,    -   2. —(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or mono-, di-        or trisubstituted independently of one another by R¹⁴,    -   3. —C(O)—NR⁴R⁵,    -   4. a 5- to 7-membered cyclic group chosen from the group        pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene,        dihydropyridine, tetrahydropyridine, piperidine, 1,3-dioxolane,        2-imidazoline, imidazolidine, 4,5-dihydro-1,3-oxazol,        1,3-oxazolidine, 4,5-dihydro-1,3-thiazole, 1,3-thiazolidine,        perhydro-1,4-dioxane, piperazine, perhydro-1,4-oxazine        (morpholine), perhydro-1,4-thiazine (thiomorpholine),        perhydroazepine, indoline, isoindoline,        1,2,3,4-tetrahydroquinoline, and 1,2,3,4-tetrahydroisoquinoline,        wherein said cyclic group is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹⁴,    -   5. —(C₆-C₁₄)-aryl, wherein aryl is chosen from the group phenyl,        naphthyl, biphenylyl, fluorenyl and anthracenyl and is        unsubstituted or mono-, di- or trisubstituted independently of        one another by R¹⁴, or    -   6. —(C₆-C₁₄)-heteroaryl, wherein heteroaryl is chosen from the        group aziridine, oxirane, azetidine, pyrrole, furan, thiophene,        dioxole, imidazole, pyrazole, oxazole, isoxazole, thiazole,        isothiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole,        pyridine, pyran, thiopyran, pyridazine, pyrimidine, pyrazine,        1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine,        1,3-thiazine, 1,4-thiazine, 1,2,3-triazine, 1,2,4-triazine,        1,3,5-triazine, azepine, 1,2-diazepine, 1,3-diazepine,        1,4-diazepine, indole, isoindole, benzofuran, benzothiophene,        1,3-benzodioxole, indazole, chromane, benzimidazole,        benzoxazole, benzothiazole, quinoline, isoquinoline,        isochromane, cinnoline, quinazoline, quinoxaline, phthalazine,        pteridine pyridyl, pyridopyridines, pyridoimidazoles,        pyridopyrimidines and purine, wherein said heteroaryl is        unsubstituted or mono-, di- or trisubstituted independently of        one another by R¹⁴,        in all its stereoisomeric forms and mixtures thereof in any        ratio, and its physiologically tolerable salts.

In still another embodiment, the compounds of formula I are defined asfollows:

-   R⁰ is phenyl, wherein phenyl is unsubstituted or mono- or    disubstituted independently of one another by R², or    -   pyridyl, wherein pyridyl is unsubstituted or mono-,        disubstituted independently of one another by R²,-   R² is halogen or —CN,-   Q is a direct bond-   Q′ is —O—,-   X is ethylene,-   W is phenyl or pyridyl, wherein W is unsubstituted or mono-, di- or    trisubstituted independently of one another by R¹,    provided that Q′ and U are in a 1,2- or 1,3- substitution    relationship with respect to each other and the 2 position is    unsubstituted;-   R¹ is halogen, —NO₂, —CN, —NH₂, (C₁-C₄)-alkylamino-, wherein alkyl    is unsubstituted or mono-, di- or trisubstituted independently of    one another by R¹³, —OH, —SO₂—NH₂, (C₁-C₄)-alkyloxy-, wherein alkyl    is unsubstituted or mono-, di- or trisubstituted independently of    one another by R¹³, (C₆-C₁₄)-aryl, wherein aryl is chosen from the    group phenyl, naphthyl, biphenylyl, fluorenyl and anthracenyl and is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, (C₁-C₄)-alkyl-, wherein alkyl is unsubstituted or    mono-, di- or trisubstituted independently of one another by R¹³,    (C₁-C₄)-alkylsulfonyl-, wherein alkyl is unsubstituted or mono-, di-    or trisubstituted independently of one another by R¹³,    bis[(C₁-C₄)-alkyl]amino, wherein alkyl is unsubstituted or mono-,    di- or trisubstituted independently of one another by R¹³,    —C(O)—NH₂, —C(O)—OH, —C(O)—(C₁-C₄)-alkyl, wherein alkyl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, —C(O)—NH—(C₁-C₄)-alkyl, wherein alkyl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, —C(O)—NH—[(C₁-C₄)-alkyl]₂, wherein alkyl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, —C(NH)—NH₂, ureido, —(C₁-C₄)-alkylthio, wherein    alkylthio is unsubstituted or mono-, di- or trisubstituted    independently of one another by R¹³, or R¹¹R¹²N—,-   R¹¹ and R¹² together with the nitrogen atom to which they are bonded    form a residue chosen from the group piperidine, morpholine,    piperazine, thiomorpholine, pyrrolidine, pyrrolidinone, and    ketopiperazine,-   R¹³ is halogen, —CN, —(C₁-C₄)-alkyl, —(C₁-C₄)-alkyloxy, —CF₃,    —C(O)—NH₂ or —NH₂,-   R¹⁰ is hydrogen atom or methyl,-   U is —(CH₂)_(m)—C(O)—NR¹⁰—(CH₂)_(n), wherein n is zero, 1 or 2, m is    zero or 1,-   R⁴ and R⁵ are independently of one another identical or different    and are hydrogen atom, —(C₁-C₆)-alkyl, wherein alkyl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, —(C₆-C₁₄)-phenyl-(C₁-C₄)-alkyl-, wherein alkyl and    phenyl independently from one another are unsubstituted or mono-,    di- or trisubstituted by R¹³, —(C₆-C₁₄)-phenyl-, wherein phenyl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, —(C₆-C₁₄)-heteroaryl, wherein heteroaryl is chosen    from the group aziridine, oxirane, azetidine, pyrrole, furan,    thiophene, dioxole, imidazole, pyrazole, oxazole, isoxazole,    thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole,    pyridine, pyran, thiopyran, pyridazine, pyrimidine, pyrazine,    1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine, 1,3-thiazine,    1,4-thiazine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine,    azepine, 1,2-diazepine, 1,3-diazepine, and 1,4-diazepine and is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³ or —(C₆-C₁₄)-heteroaryl-(C₁-C₄) -alkyl-, wherein    alkyl and heteroaryl are as defined above and independently from one    another are unsubstituted or mono-, di- or trisubstituted by R¹³, or-   R⁴ and R⁵ together with the nitrogen atom to which they are bonded    form a residue chosen from the group aziridine, oxirane, azetidine,    pyrrole, furan, thiophene, dioxole, imidazole, pyrazole, oxazole,    isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole,    tetrazole, pyridine, pyran, thiopyran, pyridazine, pyrimidine,    pyrazine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine,    1,3-thiazine, 1,4-thiazine, 1,2,3-triazine, 1,2,4-triazine,    1,3,5-triazine, azepine, 1,2-diazepine, 1,3-diazepine, and    1,4-diazepine, wherein said residue is unsubstituted or mono-, di-    or trisubstituted independently of one another by R¹³,-   G is a direct bond, —(CH₂)_(m), —(CH₂)_(m)—C(O)—NR¹⁰—(CH₂)_(n),    —(CH₂)_(m)—NR¹⁰—C(O)—NR¹⁰—(CH₂)_(n), —(CH₂)_(m)—NR¹⁰—C(O)—(CH₂)_(n),    —(CH₂)_(m)—C(O)—(CH₂)_(n), —(CH₂)_(m)—SO₂—NR¹⁰—(CH₂)_(n), or    —(CH₂)_(m)—NR¹⁰—SO₂—(CH₂)_(n)    -   wherein n, m, and R¹⁰ are as defined above-   V is    -   1. a 5- to 7-membered cyclic group chosen from the group        pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene,        dihydropyridine, tetrahydropyridine, piperidine, 1,3-dioxolane,        2-imidazoline, imidazolidine, 4,5-dihydro-1,3-oxazol,        1,3-oxazolidine, 4,5-dihydro-1,3-thiazole, 1,3-thiazolidine,        perhydro-1,4-dioxane, piperazine, perhydro-1,4-oxazine        (morpholine), perhydro-1,4-thiazine (thiomorpholine),        perhydroazepine, indoline, isoindoline,        1,2,3,4-tetrahydroquinoline, and 1,2,3,4-tetrahydroisoquinoline,        wherein said cyclic group is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹⁴,    -   2. —(C₆-C₁₄)-aryl, wherein aryl is chosen from the group phenyl,        naphthyl, biphenylyl, fluorenyl and anthracenyl and is        unsubstituted or mono-, di- or trisubstituted independently of        one another by R¹⁴, or    -   3. —(C₆-C₁₄)-heteroaryl, wherein heteroaryl is chosen from the        group aziridine, oxirane, azetidine, pyrrole, furan, thiophene,        dioxole, imidazole, pyrazole, oxazole, isoxazole, thiazole,        isothiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole,        pyridine, pyran, thiopyran, pyridazine, pyrimidine, pyrazine,        1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine,        1,3-thiazine, 1,4-thiazine, 1,2,3-triazine, 1,2,4-triazine,        1,3,5-triazine, azepine, 1,2-diazepine, 1,3-diazepine,        1,4-diazepine, indole, isoindole, benzofuran, benzothiophene,        1,3-benzodioxole, indazole, chromane, benzimidazole,        benzoxazole, benzothiazole, quinoline, isoquinoline,        isochromane, cinnoline, quinazoline, quinoxaline, phthalazine,        pteridine pyridyl, pyridopyridines, pyridoimidazoles,        pyridopyrimidines and purine, wherein said heteroaryl is        unsubstituted or mono-, di- or trisubstituted independently of        one another by R¹⁴,-   R¹⁴ is halogen, —OH, —NR⁴R⁵, ═O, —(C₁-C₄)-alkyl, —(C₁-C₄)-alkoxyl,    —C(O)—OH, —CN, —C(O)—O—(C₁-C₄)-alkyl, —C(O)—NR⁴R⁵,    —(C₁-C₈)-alkylsulfonyl, —C(O)—NH₂, —SO₂—NR⁴R⁵,    —C(O)—NH—(C₁-C₈)-alkyl, —C(O)—NH—[(C₁-C₈)-alkyl]₂, wherein R⁴ or R⁵    are as defined above, and-   M is    -   1. a hydrogen atom,    -   2. —(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or mono-, di-        or trisubstituted independently of one another by R¹⁴,    -   3. —C(O)—NR⁴R⁵,    -   4. a 5- to 7-membered cyclic group chosen from the group        pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene,        dihydropyridine, tetrahydropyridine, piperidine, 1,3-dioxolane,        2-imidazoline, imidazolidine, 4,5-dihydro-1,3-oxazol,        1,3-oxazolidine, 4,5-dihydro-1,3-thiazole, 1,3-thiazolidine,        perhydro-1,4-dioxane, piperazine, perhydro-1,4-oxazine        (morpholine), perhydro-1,4-thiazine (thiomorpholine),        perhydroazepine, indoline, isoindoline,        1,2,3,4-tetrahydroquinoline, and 1,2,3,4-tetrahydroisoquinoline,        wherein said cyclic group is unsubstituted or mono-, di- or        trisubstituted independently of one another by R¹⁴,    -   5. —(C₆-C₁₄)-aryl, wherein aryl is chosen from the group phenyl,        naphthyl, biphenylyl, fluorenyl and anthracenyl and is        unsubstituted or mono-, di- or trisubstituted independently of        one another by R¹⁴, or    -   6. —(C₆-C₁₄)-heteroaryl, wherein heteroaryl is chosen from the        group aziridine, oxirane, azetidine, pyrrole, furan, thiophene,        dioxole, imidazole, pyrazole, oxazole, isoxazole, thiazole,        isothiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole,        pyridine, pyran, thiopyran, pyridazine, pyrimidine, pyrazine,        1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine,        1,3-thiazine, 1,4-thiazine, 1,2,3-triazine, 1,2,4-triazine,        1,3,5-triazine, azepine, 1,2-diazepine, 1,3-diazepine,        1,4-diazepine, indole, isoindole, benzofuran, benzothiophene,        1,3-benzodioxole, indazole, chromane, benzimidazole,        benzoxazole, benzothiazole, quinoline, isoquinoline,        isochromane, cinnoline, quinazoline, quinoxaline, phthalazine,        pteridine pyridyl, pyridopyridines, pyridoimidazoles,        pyridopyrimidines and purine, wherein said heteroaryl is        unsubstituted or mono-, di- or trisubstituted independently of        one another by R¹⁴,        in all its stereoisomeric forms and mixtures thereof in any        ratio, and its physiologically tolerable salts.

In a another embodiment, the compounds of formula I are defined asfollows:

-   R⁰ is phenyl, wherein phenyl is unsubstituted or mono- or    disubstituted independently of one another by R², or    -   pyridyl, wherein pyridyl is unsubstituted or mono-,        disubstituted independently of one another by R²,-   R² is chlorine,-   Q is a direct bond-   Q′ is —O—,-   X is ethylene,-   W is phenyl or pyridyl, wherein W is unsubstituted or mono-, di- or    trisubstituted independently of one another by R¹,-   provided that Q′ and U are in a 1,2- or 1,3- substitution    relationship with respect to each other and the 2 position is    unsubstituted;-   R¹ is halogen, —NO₂, —CN, —NH₂, (C₁-C₄)-alkylamino-, wherein alkyl    is unsubstituted or mono-, di- or trisubstituted independently of    one another by R¹³, —OH, —SO₂—NH₂, (C₁-C₄)-alkyloxy-, wherein alkyl    is unsubstituted or mono-, di- or trisubstituted independently of    one another by R¹³, phenyl, wherein phenyl is unsubstituted or    mono-, di- or trisubstituted independently of one another by R¹³,    (C₁-C₄)-alkyl-, wherein alkyl is unsubstituted or mono-, di- or    trisubstituted independently of one another by R¹³,    (C₁-C₄)-alkylsulfonyl-, wherein alkyl is unsubstituted or mono-, di-    or trisubstituted independently of one another by R¹³,    bis[(C₁-C₄)-alkyl]amino, wherein alkyl is unsubstituted or mono-,    di- or trisubstituted independently of one another by R¹³,    —C(O)—NH₂, —C(O)—OH, —C(O)—(C₁-C₄)-alkyl, wherein alkyl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, —C(O)—NH—(C₁-C₄)-alkyl, wherein alkyl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, —C(O)—NH—[(C₁-C₄)-alkyl]₂, wherein alkyl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, —C(NH)—NH₂, ureido, —(C₁-C₄)-alkylthio, wherein    alkylthio is unsubstituted or mono-, di- or trisubstituted    independently of one another by R¹³, or R¹¹R¹²N—,-   R¹¹ and R¹² together with the nitrogen atom to which they are bonded    form a residue chosen from the group pyridine, phenyl, pyrazine,    pyrimidine, pyran, triazole, tetrahydropyridine, pyrrolidine,    tetrazole, imidazole, imidazolin, furopyridine, cyclic guanidinium,    pyrrolopyridine, and oxadiazole,-   R¹³ is halogen, —CN, —(C₁-C₄)-alkyl, —(C₁-C₄)-alkyloxy, —CF₃,    —C(O)—NH₂ or —NH₂,-   R¹⁰ is hydrogen atom or methyl,-   U is —(CH₂)_(m)—C(O)—NR¹⁰—(CH₂)_(n), wherein n is zero, 1 or 2, m is    zero or 1,-   R⁴ and R⁵ are independently of one another identical or different    and are hydrogen atom, —(C₁-C₆)-alkyl, wherein alkyl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, —(C₆-C₁₄)-phenyl-(C₁-C₄)-alkyl-, wherein alkyl and    phenyl independently from one another are unsubstituted or mono-,    di- or trisubstituted by R¹³, —(C₆-C₁₄)-phenyl-, wherein phenyl is    unsubstituted or mono-, di- or trisubstituted independently of one    another by R¹³, heteroaryl chosen from the group pyridine, pyrazine,    pyrimidine, pyran, triazole, tetrahydropyridine, pyrrolidine,    tetrazole, imidazole, imidazolin, furopyridine, cyclic guanidinium,    pyrrolopyridine, and oxadiazole, wherein heteroaryl is unsubstituted    or mono-, di- or trisubstituted independently of one another by R¹³,    or-   R⁴ and R⁵ together with the nitrogen atom to which they are bonded    form a residue chosen from the group aziridine, oxirane, azetidine,    pyrrole, furan, thiophene, dioxole, imidazole, pyrazole, oxazole,    isoxazole, thiazole, isothiazole, 1,2,3-triazole, 1,2,4-triazole,    tetrazole, pyridine, pyran, thiopyran, pyridazine, pyrimidine,    pyrazine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, 1,2-thiazine,    1,3-thiazine, 1,4-thiazine, 1,2,3-triazine, 1,2,4-triazine,    1,3,5-triazine, azepine, 1,2-diazepine, 1,3-diazepine, and    1,4-diazepine, wherein said residue is unsubstituted or mono-, di-    or trisubstituted independently of one another by R¹³,-   G is a direct bond, —(CH₂)_(m), —(CH₂)_(m)—C(O)—NR¹⁰—(CH₂)_(n),    —(CH₂)_(m)—C(O)—(CH₂)_(n), —(CH₂)_(m)—NR¹⁰—C(O)—NR¹⁰—(CH₂)_(n),    —(CH₂)_(m)—NR¹⁰—C(O)—(CH₂)_(n), —(CH₂)_(m)—SO₂—NR¹⁰—(CH₂)_(n) or    —(CH₂)_(m)—NR¹⁰—SO₂—(CH₂)_(n),    -   wherein n, m, and R¹⁰ are as defined above;-   V is tetrahydropyridine, piperidine, phenyl, or piperazine, wherein    said groups are unsubstituted or mono-, di- or trisubstituted    independently of one another by R¹⁴;-   R¹⁴ is halogen, —OH, —NR⁴R⁵, ═O, —(C₁-C₄)-alkyl, —(C₁-C₄)-alkoxyl,    —C(O)—OH, —CN, —C(O)—O—(C₁-C₄)-alkyl, —C(O)—NR⁴R⁵,    —(C₁-C₈)-alkylsulfonyl, —C(O)—NH₂, —SO₂—NR⁴R⁵,    —C(O)—NH—(C₁-C₈)-alkyl, —C(O)—NH—[(C₁-C₈)-alkyl]₂, wherein R⁴ or R⁵    are as defined above, and-   M is    -   1. a hydrogen atom,    -   2. —(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or mono-, di-        or trisubstituted independently of one another by R¹⁴,    -   3. —C(O)—NR⁴R⁵, or    -   4. or a residue chosen from the group pyridine, phenyl,        pyrazine, pyrimidine, pyran, triazole, tetrahydropyridine,        pyrrolidine, tetrazole, imidazole, imidazolin, furopyridine,        cyclic guanidinium, pyrrolopyridine, and oxadiazole,        in all its stereoisomeric forms and mixtures thereof in any        ratio, and its physiologically tolerable salts.

In another embodiment, the invention includes compounds of formula IIthat are defined as follows:

-   -   wherein A is carbon or nitrogen, wherein the carbon can be        unsubstituted or substituted by Cl, F, or Br, and    -   R1, R2, and R3 independent from each other are hydrogen, F, Cl,        —O—CH₃, —CH₃, —C(O)—N(CH₂—CH₃)₂, —C(O)—NH₂, or        —C(O)—NH—CH₂-piperidine-pyridine,        in all its stereoisomeric forms and mixtures thereof in any        ratio, and its physiologically tolerable salts.

In general, the meaning of any group, residue, heteroatom, number, etc.that may occur more than once in the compounds of the formula I, isindependent of the meaning of this group, residue, heteroatom, number,etc. in any other occurrence. All groups, residues, heteroatoms, numbersetc. that may occur more than once in the compounds of the formula I maybe identical or different.

As used herein, the term alkyl is to be understood in the broadest senseto mean hydrocarbon residues that can be linear, i.e., straight-chain,or branched and which can be acyclic or cyclic residues or comprise anycombination of acyclic and cyclic subunits. Further, the term alkyl asused herein expressly includes saturated groups as well as unsaturatedgroups.

Unsaturated groups may contain one or more, for example one, two orthree, double bonds and/or triple bonds, provided that the double bondsare not located within a cyclic alkyl group in such a manner that anaromatic system results. All these statements also apply if an alkylgroup occurs as a substituent on another residue, for example in analkyloxy, alkyloxycarbonyl, or arylalkyl residue. Examples of alkylresidues containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms are methyl,ethyl, propyl, butyl, pentyl, hexyl, heptyl or octyl residues, and then-isomers of any of these residues, isopropyl, isobutyl, 1-methylbutyl,isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl,isohexyl, sec-butyl, tBu, tert-pentyl, sec-butyl, tert-butyl ortert-pentyl.

Unsaturated alkyl residues include, for example, alkenyl residues suchas vinyl, 1-propenyl, 2-propenyl (=allyl), 2-butenyl, 3-butenyl,2-methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl or 1,3-pentadienyl; oralkynyl residues such as ethynyl, 1-propynyl, 2-propynyl (=propargyl) or2-butynyl. Alkyl residues can also be unsaturated when they aresubstituted.

Examples of cyclic alkyl residues are cycloalkyl residues containing 3,4, 5 or 6 ring carbon atoms like cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, which can also be substituted and/or unsaturated.Unsaturated cyclic alkyl groups and unsaturated cycloalkyl groups, e.g.,cyclopentenyl or cyclohexenyl, can be bonded via any carbon atom.

Of course, a cyclic alkyl group has to contain at least three carbonatoms, and an unsaturated alkyl group has to contain at least two carbonatoms. Thus, a group like (C₁-C₈)-alkyl is to be understood ascomprising, among others, saturated acyclic (C₁-C₈)-alkyl,(C₃-C₆)-cycloalkyl, and unsaturated (C₂-C₈)-alkyl like (C₂-C₈)-alkenylor (C₂-C₈)-alkynyl. Similarly, a group like (C₁-C₄)-alkyl is to beunderstood as comprising, among others, saturated acyclic (C₁-C₄)-alkyl,and unsaturated (C₂-C₄)-alkyl like (C₂-C₄)-alkenyl or (C₂-C₄)-alkynyl.

Unless stated otherwise, the term alkyl may comprise acyclic saturatedhydro-carbon residues that have from one to six carbon atoms and may belinear or branched. A typical group of saturated acyclic alkyl residuesis formed by (C₁-C₄)-alkyl residues like methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl and tBu.

Unless stated otherwise, and irrespective of any specific substituentsbonded to alkyl groups that are indicated in the definition of thecompounds of the formula I, alkyl groups can generally be unsubstitutedor substituted by one or more, for example one, two, or three, identicalor different substituents. Any kind of substituents present insubstituted alkyl residues can be present in any desired positionprovided that the substitution does not lead to an unstable molecule.Examples of substituted alkyl residues are alkyl residues in which oneor more, for example 1, 2, or 3, hydrogen atoms are replaced withhalogen atoms, e.g., fluorine atoms.

The term mono- or bicyclic 5- to 14-membered aryl group includes, forexample, phenyl, biphenyl or napthyl.

The term mono- or bicyclic 5- to 14-membered heteroaryl refers to(C₅-C₁₄)-aryl in which one or more of the 5 to 10 ring carbon atoms arereplaced by heteroatoms such as nitrogen, oxygen or sulphur. Examplesinclude pyridyl; such as 2-pyridyl, 3-pyridyl or 4-pyridyl; pyrrolyl;such as 2-pyrrolyl and 3-pyrrolyl; furyl; such as 2-furyl and 3-furyl;thienyl; such as 2-thienyl and 3-thienyl; imidazolyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridazinyl,pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, phthalazinyl,quinolyl, isoquinolyl or quinoxalinyl or phenylpyridyl.

The terms R¹¹ and R¹², together with the nitrogen atom to which they arebonded, form a saturated or unsaturated 5- to 6-membered monocyclicheterocyclic ring, and refer to, e.g., pyrrol, piperidine, pyrrolidine,morpholine, piperazine, pyridine, pyrimidine, imidazole orthiomorpholine.

The term aryl refers to a monocyclic or polycyclic hydrocarbon residuein which at least one carbocyclic ring is present that has a conjugatedpi electron system. In a (C₆-C₁₄) -aryl residue, 6 to 14 ring carbonatoms are present. Examples of (C₆-C₁₄)-aryl residues include phenyl,naphthyl, biphenylyl, fluorenyl or anthracenyl. Unless stated otherwise,and irrespective of any specific substituents bonded to aryl groups thatare indicated in the definition of the compounds of the formula I, arylresidues, (e.g., phenyl, naphthyl or fluorenyl), can in general beunsubstituted or substituted by one or more, for example one, two orthree, identical or different substituents. Aryl residues can be bondedvia any desired position, and in substituted aryl residues thesubstituents can be located in any desired position.

Unless stated otherwise, and irrespective of any specific substituentsbonded to aryl groups that are indicated in the definition of thecompounds of the formula I, substituents that can be present insubstituted aryl groups are, for example, (C₁-C₈)-alkyl; (C₁-C₄)-alkyl,such as methyl, ethyl or tBu, hydroxyl; (C₁-C₈)-alkyloxy;(C₁-C₄)-alkyloxy, such as methoxy, ethoxy or tert-butoxy,methylenedioxy, ethylenedioxy; F; Cl; Br; I; cyano; nitro;trifluoromethyl; trifluoromethoxy; hydroxymethyl; formyl; acetyl; amino;mono- or di-(C₁-C₄) -alkylamino; ((C₁-C₄)-alkyl)carbonylamino likeacetylamino; hydroxycarbonyl; ((C₁-C₄) -alkyloxy)carbonyl; carbamoyl;benzyl optionally substituted in the phenyl group; optionallysubstituted phenyl; optionally substituted phenoxy; or benzyloxyoptionally substituted in the phenyl group. A substituted aryl groupthat is present in a specific position of the compounds of formula I canindependently of other aryl groups be substituted by substituents chosenfrom any desired subgroup of the substituents listed before and/or inthe specific definition of that group. For example, a substituted arylgroup may be substituted by one or more identical or differentsubstituents chosen from (C₁-C₄)-alkyl, hydroxyl, (C₁-C₄)-alkyloxy, F,Cl, Br, I, cyano, nitro, trifluoromethyl, amino, phenyl, benzyl, phenoxyand benzyloxy. In general, not more than two nitro groups are present inthe compounds of the formula I.

In monosubstituted phenyl residues the substituent can be located in the2-position, the 3-position or the 4-position, with the 3-position andthe 4-position being commonly used. If a phenyl group carries twosubstituents, they can be located in 2,3-position, 2,4-position,2,5-position, 2,6-position, 3,4-position or 3,5-position. In phenylresidues carrying three substituents the substituents can be located in2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position,2,4,6-position, or 3,4,5-position. Naphthyl residues can be 1-naphthyland 2-naphthyl. In substituted naphthyl residues the substituents can belocated in any positions, for example, in monosubstituted 1-naphthylresidues in the 2-, 3-, 4-, 5-, 6-, 7-, or 8-position and inmonosubstituted 2-naphthyl residues in the 1-, 3-, 4-, 5-, 6-, 7-, or8-position. Biphenylyl residues can be 2-biphenylyl, 3-biphenylyl and4-biphenylyl. Fluorenyl residues can be 1-, 2-, 3-, 4- or 9-fluorenyl.In monosubstituted fluorenyl residues bonded via the 9-position thesubstituent is typically present in the 1-, 2-, 3- or 4-position.

A 4-15 membered mono- or polycyclic group, which can contain, zero, one,two, three or four heteroatoms, such as nitrogen, sulphur, or oxygen,comprises groups containing 4 to 15 ring atoms in the parent monocyclicor bicyclic carbocyclic or heterocyclic ring system. In monocyclicgroups, the carbocyclic or heterocyclic ring may be a 5-membered,6-membered or 7-membered ring. In one embodiment, it is a 5-membered or6-membered ring. In bicyclic groups, two fused rings may bepresent inwhich one is a 5-membered ring or 6-membered carbocyclic or heterocyclicring, and the other is a 5-membered or 6-membered heterocyclic orcarbocyclic ring (i.e., the bicyclic ring typically contains 8, 9 or 10ring atoms, generally 9 or 10 ring atoms). It comprises saturatedcarbocyclic or heterocyclic ring systems that do not contain any doublebonds within the rings, as well as mono-unsaturated and poly-unsaturatedcarbocyclic or heterocyclic ring systems that contain one or more, forexample one, two, three, four or five, double bonds within the ringsprovided that the resulting system is stable. Unsaturated rings may benon-aromatic or aromatic, i.e., double bonds within the rings in thisgroup may be arranged in such a manner that a conjugated pi electronsystem results. Aromatic rings in a group may be 5-membered or6-membered rings, i.e., aromatic groups in a group contain 5 to 10 ringatoms. Aromatic rings in this group thus comprise 5-membered and6-membered monocyclic carbocycles or heterocycles and bicycliccarbocycles or heterocycles composed of two 5-membered rings, one5-membered ring and one 6-membered ring, or two 6-membered rings. Inbicyclic aromatic groups one or both rings may contain heteroatoms.Aromatic groups may also be referred to by the customary term aryl orheteroaryl for which all the definitions and explanations above andbelow correspondingly apply.

Examples of carbocyclic groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl,decahydronaphthaline, twistan (=tricyclo[4.4.0.0^(3,8)]decan),adamantane (=tricyclo[3.3.1.1^(3,7)]decan), noradamantane(=tricyclo[3.3.1.0^(3,7)]nonane), tricyclo[2.2.1.0^(2,6)]heptane,tricyclo[5.3.2.0^(4,9)]dodecane, tricyclo[5.4.0.0^(2,9)]undecane ortricyclo[5.5.1.0^(3,11)]tridecane.

In heterocyclic groups, 1, 2, 3 or 4 identical or different ringheteroatoms chosen from nitrogen, oxygen and sulphur may be present. Inthese groups, one or two identical or different heteroatoms may bechosen from nitrogen, oxygen and sulphur. The ring heteroatoms may bepresent in any desired number and in any position with respect to eachother provided that the resulting heterocyclic system is known in theart and is stable and suitable as a subgroup in a drug substance.Examples of parent structures of heterocycles from which the 4-15membered mono- or polycyclic group can be derived are aziridine,oxirane, azetidine, pyrrole, furan, thiophene, dioxole, imidazole,pyrazole, oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole,1,2,4-triazole, tetrazole, pyridine, pyran, thiopyran, pyridazine,pyrimidine, pyrazine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine,1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,2,3-triazine,1,2,4-triazine, 1,3,5-triazine, azepine, 1,2-diazepine, 1,3-diazepine,1,4-diazepine, indole, isoindole, benzofuran, benzothiophene,1,3-benzodioxole, indazole, benzimidazole, benzoxazole, benzothiazole,quinoline, isoquinoline, chromane, isochromane, cinnoline, quinazoline,quinoxaline, phthalazine, pyridoimidazoles, pyridopyridines,pyridopyrimidines, purine, pteridine etc. as well as ring systems thatresult from the listed heterocycles by fusion (or condensation) of acarbocyclic ring, for example benzo-fused, cyclopenta-fused,cyclohexa-fused or cyclohepta-fused derivatives of these heterocycles.

The fact that many of the before-listed names of heterocycles are thechemical names of unsaturated or aromatic ring systems does not implythat the, 4-15 membered mono- or polycyclic group could only be derivedfrom the respective unsaturated ring system. The names here only serveto describe the ring systems by ring size, the number of theheteroatoms, and their relative positions.

As explained above, the 4-15 membered mono- or polycyclic groups can besaturated or partially unsaturated or aromatic, and can thus be derivednot only from the before-listed heterocycles themselves but also fromall their partially or completely hydrogenated analogues, and their morehighly unsaturated analogues if desired. As examples of completely orpartially hydrogenated analogues of the before-listed heterocycles fromwhich this group may be derived, the following are useful examples:pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene,dihydropyridine, tetrahydropyridine, piperidine, 1,3-dioxolane,2-imidazoline, imidazolidine, 4,5-dihydro-1,3-oxazol, 1,3-oxazolidine,4,5-dihydro-1,3-thiazole, 1,3-thiazolidine, perhydro-1,4-dioxane,piperazine, perhydro-1,4-oxazine (=morpholine), perhydro-1,4-thiazine(=thiomorpholine), perhydroazepine, indoline, isoindoline,1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, etc.

The 4-15 membered mono- or polycyclic group may be bonded via any ringcarbon atom, and in the case of nitrogen heterocycles via any suitablering nitrogen atom. Thus, for example, a pyrrolyl residue can be1-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl, a pyrrolidinyl residue can bepyrrolidin-1-yl (=pyrrolidino), pyrrolidin-2-yl or pyrrolidin-3-yl, apyridinyl residue can be pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, apiperidinyl residue can be piperidin-1-yl (=piperidino), piperidin-2-yl,piperidin-3-yl or piperidin-4-yl. Furyl can be 2-furyl or 3-furyl,thienyl can be 2-thienyl or 3-thienyl, imidazolyl can be imidazol-1-yl,imidazol-2-yl, imidazol-4-yl or imidazol-5-yl, 1,3-oxazolyl can be1,3-oxazol-2-yl, 1,3-oxazol-4-yl or 1,3-oxazol-5-yl, 1,3-thiazolyl canbe 1,3-thiazol-2-yl, 1,3-thiazol-4-yl or 1,3-thiazol-5-yl, pyrimidinylcan be pyrimidin-2-yl, pyrimidin-4-yl (=6-pyrimidinyl) or 5-pyrimidinyl,piperazinyl can be piperazin-1-yl (=piperazin-4-yl=piperazino) orpiperazin-2-yl. Indolyl can be indol-1-yl, indol-2-yl, indol-3-yl,indol-4-yl, indol-5-yl, indol-6-yl or indol-7-yl. Similarlybenzimidazolyl, benzoxazolyl and benzothiazol residues can be bonded viathe 2-position and via any of the positions 4, 5, 6, and 7. Quinolinylcan be quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl,quinolin-6-yl, quinolin-7-yl or quinolin-8-yl, isoqinolinyl can beisoquinol-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl,isoquinolin-6-yl, isoquinolin-7-yl or isoquinolin-8-yl. In addition tobeing bonded via any of the positions indicated for quinolinyl andisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl and1,2,3,4-tetrahydroisoquinolinyl can also be bonded via the nitrogenatoms in 1-position and 2-position, respectively.

Unless stated otherwise, and irrespective of any specific substituentsbonded to the 4-15 membered mono- or polycyclic group or any otherheterocyclic groups that are indicated in the definition of thecompounds of the formula I, the 4-15 membered mono- or polycyclic groupcan be unsubstituted or substituted on ring carbon atoms with one ormore, for example one, two, three, four or five, identical or differentsubstituents like (C₁-C₈)-alkyl, (C₁-C₄)-alkyl, (C₁-C₈)-alkyloxy,(C₁-C₄)-alkyloxy, (C₁-C₄)-alkylthio, halogen, nitro, amino,((C₁-C₄)-alkyl)carbonylamino like acetylamino, trifluoromethyl,trifluoromethoxy, hydroxyl, oxo, hydroxy-(C₁-C₄)-alkyl such as, forexample, hydroxymethyl,1-hydroxyethyl, 2-hydroxyethyl, methylenedioxy,ethylenedioxy, formyl, acetyl, cyano, aminosulfonyl, methylsulfonyl,hydroxycarbonyl, aminocarbonyl, (C₁-C₄)-alkyloxycarbonyl, optionallysubstituted phenyl, optionally substituted phenoxy, benzyl optionallysubstituted in the phenyl group, benzyloxy optionally substituted in thephenyl group, etc. The substituents can be present in any desiredposition provided that a stable molecule results. Of course an oxy groupcannot be present in an aromatic ring. Each suitable ring nitrogen atomin the 4-15 membered mono- or polycyclic group can independently of eachother be unsubstituted, (i.e. carry a hydrogen atom), or can besubstituted, (i.e. carry a substituent like (C₁-C₈)-alkyl, for example(C₁-C₄)-alkyl such as methyl or ethyl, optionally substituted phenyl,phenyl-(C₁-C₄)-alkyl, for example benzyl, optionally substituted in thephenyl group, hydroxy-(C₂-C₄)-alkyl such as, for example 2-hydroxyethyl,acetyl or another acyl group, methylsulfonyl or another sulfonyl group,aminocarbonyl, (C₁-C₄)-alkyloxycarbonyl, etc.) In general, in thecompounds of the formula I, nitrogen heterocycles can also be present asN-oxides or as quaternary salts. Ring sulphur atoms can be oxidized tothe sulfoxide or to the sulfone. Thus, a tetrahydrothienyl residue, forexample, may be present as S,S-dioxotetrahydro-thienyl residue; or athiomorpholinyl residue, such as thiomorpholin-4-yl, may be present as1-oxo-thiomorpholin-4-yl or 1,1-dioxo-thiomorpholin-4-yl. A substituted4-15 membered mono- or polycyclic group that can be present in aspecific position of the compounds of formula I can independently ofother groups be substituted by substituents chosen from any desiredsubgroup of the substituents listed before and/or in the definition ofthat group.

Examples for a 5 to 7-membered monocyclic heterocyclic ring, containingat least one nitrogen atom and which is optionally substituted by oxygeninclude piperidine, morpholine, piperazine, thiomorpholine, pyrrolidine,pyrrolidinone, and ketopiperazine.

A 3-7 membered monocyclic group, containing zero, one, two, three orfour heteroatoms, such as nitrogen, sulphur or oxygen, comprises groupscontaining 3 to 7 ring atoms in the parent monocyclic carbocyclic orheterocyclic ring system. In one embodiment, the carbocyclic orheterocyclic ring is a 5-membered or a 6-membered ring.

The compounds may also comprise saturated carbocyclic or heterocyclicring systems that do not contain any double bonds within the rings, aswell as mono-unsaturated and poly-unsaturated carbocyclic orheterocyclic ring systems that contain one or more, (e.g., one, two orthree double bonds within the ring) provided that the resulting ringsystem is stable.

Unsaturated rings may be non-aromatic or aromatic, i.e., double bondswithin the rings in this group may be arranged in such a manner that aconjugated pi electron system results. Aromatic rings in this groupcomprise 5-membered and 6-membered monocyclic carbocycles orheterocycles. Aromatic groups may also be referred to by the customaryterm aryl or heteroaryl, for which all the definitions and explanationsabove and below correspondingly apply.

Examples of carbocyclic groups include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

In heterocyclic groups, 1, 2, 3 or 4 identical or different ringheteroatoms chosen from nitrogen, oxygen and sulphur are present. Inthese groups, one or two identical or different heteroatoms chosen fromnitrogen, oxygen and sulphur are present. The ring heteroatoms can bepresent in any desired number and in any position with respect to eachother provided that the resulting heterocyclic system is known in theart and is stable and suitable as a subgroup in a drug substance.Examples of parent structures of heterocycles from which the 3-7membered monocyclic group can be derived are aziridine, oxirane,azetidine, pyrrole, furan, thiophene, dioxole, imidazole, pyrazole,oxazole, isoxazole, thiazole, isothiazole, 1,2,3-triazole,1,2,4-triazole, tetrazole, pyridine, pyran, thiopyran, pyridazine,pyrimidine, pyrazine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine,1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,2,3-triazine,1,2,4-triazine, 1,3,5-triazine, azepine, 1,2-diazepine, 1,3-diazepine,1,4-diazepine etc.

The fact that many of the before-listed names of heterocycles are thechemical names of unsaturated or aromatic ring systems does not implythat, the 3-7 membered monocyclic group can only be derived from therespective unsaturated ring system. The names here only serve todescribe the ring system by ring size, the number of heteroatoms, andtheir relative positions. As explained above, the 3-7 memberedmonocyclic group can be saturated or partially unsaturated or aromatic;and can thus be derived not only from the before-listed heterocyclesthemselves but also from all their partially or completely hydrogenatedanalogues and also from their more highly unsaturated analogues, ifdesired. Completely or partially hydrogenated analogues of thebefore-listed heterocycles from which this group may be derived include:pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene,dihydropyridine, tetrahydropyridine, piperidine, 1,3-dioxolane,2-imidazoline, imidazolidine, 4,5-dihydro-1,3-oxazol, 1,3-oxazolidine,4,5-dihydro-1,3-thiazole, 1,3-thiazolidine, perhydro-1,4-dioxane,piperazine, perhydro-1,4-oxazine (=morpholine), perhydro-1,4-thiazine(=thiomorpholine), perhydroazepine etc.

The 3-7 membered monocyclic group may be bonded via any ring carbonatom, and in the case of nitrogen heterocycles via any suitable ringnitrogen atom. Thus, for example, a pyrrolyl residue can be 1-pyrrolyl,2-pyrrolyl or 3-pyrrolyl, a pyrrolidinyl residue can be pyrrolidin-1-yl(=pyrrolidino), pyrrolidin-2-yl or pyrrolidin-3-yl, a pyridinyl residuecan be pyridin-2-yl, pyridin-3-yl or pyridin-4-yl, a piperidinyl residuecan be piperidin-1-yl (=piperidino), piperidin-2-yl, piperidin-3-yl orpiperidin-4-yl. Furyl can be 2-furyl or 3-furyl, thienyl can be2-thienyl or 3-thienyl, imidazolyl can be imidazol-1-yl, imidazol-2-yl,imidazol-4-yl or imidazol-5-yl, 1,3-oxazolyl can be 1,3-oxazol-2-yl,1,3-oxazol-4-yl or 1,3-oxazol-5-yl, 1,3-thiazolyl can be1,3-thiazol-2-yl, 1,3-thiazol-4-yl or 1,3-thiazol-5-yl, pyrimidinyl canbe pyrimidin-2-yl, pyrimidin-4-yl (=6-pyrimidinyl) or 5-pyrimidinyl,piperazinyl can be piperazin-1-yl (=piperazin-4-yl=piperazino) orpiperazin-2-yl. Unless stated otherwise, and irrespective of anyspecific substituents bonded to the 3-7 membered monocyclic group or anyother heterocyclic groups that are indicated in the definition of thecompounds of the formula I, the 3-7 membered rings can be unsubstitutedor substituted on ring carbon atoms with one or more, for example one,two, three, four or five, identical or different substituents like(C₁-C₈)-alkyl, (C₁-C₄)-alkyl, (C₁-C₈)-alkyloxy, (C₁-C₄)-alkyloxy,(C₁-C₄)-alkylthio, halogen, nitro, amino, ((C₁-C₄)-alkyl)carbonylaminolike acetylamino, trifluoromethyl, trifluoromethoxy, hydroxyl, oxo,hydroxy-(C₁-C₄)-alkyl such as, for example, hydroxymethyl or1-hydroxyethyl or 2-hydroxyethyl, methylenedioxy, ethylenedioxy, formyl,acetyl, cyano, aminosulfonyl, methylsulfonyl, hydroxycarbonyl,aminocarbonyl, (C₁-C₄)-alkyloxycarbonyl, optionally substituted phenyl,optionally substituted phenoxy, benzyl optionally substituted in thephenyl group, benzyloxy optionally substituted in the phenyl group, etc.The substituents can be present in any desired position provided that astable molecule results. Of course an oxy group cannot be present in anaromatic ring. Each suitable ring nitrogen atom in the 3-7 memberedmonocyclic group can independently of each other be unsubstituted (i.e.carry a hydrogen atom), or can be substituted, (i.e. carry a substituentlike (C₁-C₈)-alkyl, for example (C₁-C₄)-alkyl such as methyl or ethyl,optionally substituted phenyl, phenyl-(C₁-C₄)-alkyl, for example benzyl,optionally substituted in the phenyl group, hydroxy-(C₂-C₄)-alkyl suchas, for example 2-hydroxyethyl, acetyl or another acyl group,methylsulfonyl or another sulfonyl group, aminocarbonyl,(C₁-C₄)-alkyloxycarbonyl, etc.) In general, in the compounds of theformula I, nitrogen heterocycles can also be present as N-oxides or asquaternary salts. Ring sulphur atoms can be oxidized to the sulfoxide orto the sulfone. Thus, for example a tetrahydrothienyl residue may bepresent as a S,S-dioxotetrahydrothienyl residue; or a thiomorpholinylresidue like thiomorpholin-4-yl may be present as1-oxo-thiomorpholin-4-yl or 1,1-dioxo-thiomorpholin-4-yl. A substituted3-7 membered monocyclic group that can be present in a specific positionof the compounds of formula I can independently of other groups besubstituted by substituents chosen from any desired subgroup of thesubstituents listed before and/or in the definition of that group.

Halogen refers to fluorine, chlorine, bromine or iodine; typically,fluorine, chlorine or bromine is used. In one embodiment, the halogenis, chlorine or bromine.

Optically active carbon atoms present in the compounds of the formula Ican independently of each other have R configuration or S configuration.The compounds of the formula I can be present in the form of pureenantiomers, pure diastereomers, or a mixture of enantiomers and/ordiastereomers; for example, in the form of racemates. The presentinvention relates to pure enantiomers and mixtures of enantiomers aswell as to pure diastereomers and mixtures of diastereomers. Theinvention comprises mixtures of two or more stereoisomers of thecompounds of formula I; it also comprises all ratios of thestereoisomers in the mixtures. In case the compounds of formula I can bepresent as E isomers or Z isomers (or cis isomers or trans isomers) theinvention relates both to pure E isomers, pure Z isomers, and to E/Zmixtures in all ratios. The invention also comprises all tautomericforms of the compounds of the formula I.

Diastereomers, including E/Z isomers, can be separated into theindividual isomers, for example, by chromatography. Racemates can beseparated into the two enantiomers by customary methods, for example bychromatography on chiral phases or by resolution, for example bycrystallisation of diastereomeric salts obtained with optically activeacids or bases. Stereochemically uniform compounds of the formula I canalso be obtained by employing stereochemically uniform startingmaterials or by using stereoselective reactions.

The choice of incorporating into a compound of the formula I a buildingblock with R configuration or S configuration, or in the case of anamino acid unit present in a compound of the formula I of incorporatinga building block designated as D-amino acid or L-amino acid, can depend,for example, on the desired characteristics of the compound of theformula I. For example, the incorporation of a D-amino acid buildingblock can confer increased stability in vitro or in vivo. Theincorporation of a D-amino acid building block also can achieve adesired increase or decrease in the pharmacological activity of thecompound. In some cases it can be desirable to allow the compound toremain active for only a short period of time. In such cases, theincorporation of an L-amino acid building block in the compound canallow endogenous peptidases in an individual to digest the compound invivo, thereby limiting the individual's exposure to the active compound.A similar effect may also be observed in the compounds of the inventionby changing the configuration in another building block from Sconfiguration to R configuration or vice versa. By taking intoconsideration the medical needs one skilled in the art can determine thedesirable characteristics, for example a favourable stereochemistry, ofthe required compound of the invention.

Physiologically tolerable salts of the compounds of formula I arenon-toxic salts that are physiologically acceptable, in particularpharmaceutically utilisable salts. Such salts of compounds of theformula I containing acidic groups, for example a carboxyl group COOH,are for example alkali metal salts or alkaline earth metal salts such assodium salts, potassium salts, magnesium salts and calcium salts, andalso salts with physiologically tolerable quaternary ammonium ions suchas tetramethylammonium or tetraethylammonium, and acid addition saltswith ammonia and physiologically tolerable organic amines, such asmethylamine, dimethylamine, trimethylamine, ethylamine, triethylamine,ethanolamine or tris-(2-hydroxyethyl)amine. Basic groups contained inthe compounds of the formula I, for example amino groups or guanidinogroups, form acid addition salts, for example with inorganic acids suchas hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid orphosphoric acid, or with organic carboxylic acids and sulfonic acidssuch as formic acid, acetic acid, oxalic acid, citric acid, lactic acid,malic acid, succinic acid, malonic acid, benzoic acid, maleic acid,fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonicacid. Compounds of the formula I, which simultaneously contain a basicgroup and an acidic group, for example, a guanidino group and a carboxylgroup, can also be present as zwitterions (betaines), which are likewiseincluded in the present invention.

Salts of compounds of the formula I can be obtained by customary methodsknown to those skilled in the art, for example by combining a compoundof the formula I with an inorganic or organic acid or base in a solventor dispersant, or from other salts by cation exchange or anion exchange.The present invention also includes all salts of the compounds of theformula I which, because of low physiologically tolerability, are notdirectly suitable for use in pharmaceuticals but are suitable, forexample, as intermediates for carrying out further chemicalmodifications of the compounds of the formula I or as starting materialsfor the preparation of physiologically tolerable salts. The presentinvention furthermore includes all solvates of compounds of the formulaI, for example hydrates or adducts with alcohols.

The invention also includes derivatives and modifications of thecompounds of the formula I, for example prodrugs, protected forms, andother physiologically tolerable derivatives, as well as activemetabolites of the compounds of the formula I. The invention relates,for example, to prodrugs and protected forms of the compounds of theformula I that can be converted into compounds of the formula I underphysiological conditions. Suitable prodrugs for the compounds of theformula I, i. e. chemically modified derivatives of the compounds of theformula I having properties that are improved in a desired manner, forexample with respect to solubility, bioavailability or duration ofaction, are known to those skilled in the art. More detailed informationrelating to prodrugs is found in standard literature (see, for example,Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985, Fleisher et al.,Advanced Drug Delivery Reviews 19 (1996) 115-130; or H. Bundgaard, Drugsof the Future 16 (1991) 443, which are all incorporated herein byreference). Suitable prodrugs for the compounds of the formula I includeacyl prodrugs and carbamate prodrugs of acylatable, nitrogen-containinggroups (such as amino guanidino groups), and ester prodrugs and amideprodrugs of carboxylic acid groups that may be present in compounds ofthe formula I. In the acyl prodrugs and carbamate prodrugs, one or more(for example one or two) hydrogen atoms on nitrogen atoms in such groupsare replaced with an acyl group or a carbamate, such as a(C₁-C₆)-alkyloxycarbonyl group. Suitable acyl groups and carbamategroups for acyl prodrugs and carbamate prodrugs include, for example,the groups R^(p1)—CO— and R^(p2)O—CO—, in which R^(p1) is hydrogen,(C₁-C₁₈)-alkyl, (C₃-C₈)-cycloalkyl, (C₃-C₈)-cycloalkyl-(C₁-C₄)-alkyl-,(C₆-C₁₄)-aryl, Het-, (C₆-C₁₄)-aryl-(C₁-C₄)-alkyl- or Het-(C₁-C₄)-alkyl-and in which R^(p2) has the meanings indicated for R^(p1) with theexception of hydrogen.

The present invention also relates to processes of preparation by whichthe compounds of the formula I are obtainable, and which comprisescarrying out one or more of the synthesis steps described below. Thecompounds of the formula I can generally be prepared using proceduresdescribed below, together with synthetic methods known to those skilledin the art of organic synthesis (see, e.g., J. March, Advanced OrganicChemistry, Fourth Edition, John Wiley & Sons, 1992), or variationsthereon as appreciated by those skilled in the art. For example, in thecourse of a convergent synthesis, linkage of two or more fragments thatcan be derived retrosynthetically from the formula I and the synthesisof those fragments is known to those skilled in the art. In the courseof the preparation of the compounds of the formula I it can generally beadvantageous or necessary to introduce functional groups that couldavoid undesired reactions or side reactions in the respective synthesisstep, in the form of precursor groups that are later converted into thedesired functional groups, or to temporarily block functional groups bya protective group strategy suited to the synthesis problem. Suchstrategies are well known to those skilled in the art (see, for example,Greene and Wuts, Protective Groups in Organic Synthesis, Wiley, 1991 orP. Kocienski, Protecting Groups, Thieme 1994). Examples of precursorgroups include nitro groups and cyano groups, which can later beconverted by reduction, for example by catalytic hydrogenation, intoamino groups and aminomethyl groups, respectively. Protective groups canalso have the meaning of a solid phase, and cleavage from the solidphase results in the removal of the protective group. The use of suchtechniques is known to those skilled in the art (Burgess K (Ed.) SolidPhase Organic Synthesis, New York: Wiley, 2000). For example, a phenolichydroxyl group can be attached to a trityl-polystyrene resin, whichserves as a protecting group, and the molecule may be cleaved from thisresin by treatment with TFA at a later stage of the synthesis.

For example, for the preparation of one of the compounds of the formulaI, in which W is phenyl, and in which U has the meaning of—(CH₂)₀C(O)NR¹⁰(CH₂)₁—, a building block of the formula XI,

in which R⁰, Q, Q′, X, are as defined above for the compounds of theformula I but functional groups of the formula XI can optionally also bepresent in the form of precursor groups or can be protected byprotective groups known to those skilled in the art, e.g. an amino groupcan be protected with a tert.-butyloxycarbonyl group or abenzyloxycarbonyl group. R¹′, R^(1″), R^(1′″), R^(1″″), are defined ashydrogen or as R¹ which, has the same meaning as in formula I, but canoptionally also be present in the form of precursor groups or can beprotected by protective groups known to those skilled in the art, e.g.,a hydroxyl group may be attached to a polystyrene resin, and Y is anucleophilically substitutable leaving group or a hydroxyl group, whichmay also be attached to a polystyrene resin, is reacted with a fragmentof the formula XIIH—NR¹⁰—V—G—M  (XII)in which R¹⁰, V, G, and M are as defined above for the compounds of theformula I but functional groups of the formula XII can optionally alsobe present in the form of precursor groups or can be protected byprotective groups.

The group COY in the formula XI may be the carboxylic acid group COOH oran activated carboxylic acid derivative. Y can thus be, for example,hydroxyl, halogen, such as chlorine or bromine, alkoxyl, such as methoxyor ethoxy, aryloxy, for example phenoxy or pentafluorophenoxy,phenylthio, methylthio, 2-pyridylthio or a residue of a nitrogenheterocycle bonded via a nitrogen atom. In one embodiment, Y is aresidue of an azole, such as 1-imidazolyl. Y can furthermore be, forexample, ((C₁-C₄)-alkyl)-O—CO—O— or tolylsulfonyloxy and the activatedacid derivative can thus be a mixed anhydride.

If Y is hydroxyl, then the carboxylic acid is expediently firstactivated, for example by one of the various methods used for peptidecouplings that are well known to those skilled in the art. Examples ofsuitable activation agents are O-((cyano(ethoxycarbonyl)methylene)amino)-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU);(König et al., Proc. 21st Europ. Peptide Symp. 1990 (Eds. Giralt,Andreu), Escom, Leiden 1991, p. 143),O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate (HATU) (L. A. Carpino, J. Am. Chem. Soc. 115 (1993)4397), diethylphosphoryl cyanide (DEPC);bis-(2-oxo-3-oxazolidinyl)-phosphoryl chloride (BOP-Cl) or carbodiimideslike dicyclohexylcarbodiimide or diisopropylcarbodiimide. The activationof the carboxylic acid function may also favourably be carried, forexample, by conversion of the carboxylic acid group into thepentafluorophenyl ester using dicyclohexylcarbodiimide andpentafluorophenol. Another favourable method is the activation of thecarboxylic acid group as a carbonylimidazolide withN,N-carbonyldiimidazole (CDI). A number of suitable methods for thepreparation of activated carboxylic acid derivatives are also indicatedwith details of source literature in J. March, Advanced OrganicChemistry, Fourth Edition, John Wiley & Sons, 1992. The activation andthe subsequent reaction with the compound of the formula III are usuallycarried in the presence of an inert solvent or diluent, for example DCM,chloroform, THF, diethyl ether, n-heptane, n-hexane, n-pentane,cyclohexane, diisopropyl ether, methyl tBu ether, acetonitrile, DMF,DMSO, dioxane, toluene, benzene, ethyl acetate or a mixture of thesesolvents, if appropriate, with addition of a base such as, for example,potassium tert-butoxide or tributylamine or triethylamine ordiisopropylethylamine.

The resulting product is a compound of the formula I in which functionalgroups can also be present in the form of precursor groups or can beprotected by protective groups. If any protective groups or precursorgroups are present, they may then be removed by known methods (seeGreene and Wuts, Protective Groups in Organic Synthesis, Wiley, 1991 orP. Kocienski, Protecting Groups, Thieme 1994), or converted into thedesired final groups, respectively. For example, if a carboxylic acidgroup is protected as tBu ester, and the free carboxylic acid is to beprepared as the final compound, the protective group can be removed byreaction with trifluoroacetic acid or hydrochloric acid. If desired, theobtained compounds may be subject to further reactions carried out bystandard processes. For example the compounds may be subjected toacylation reactions or esterification reactions, or the compounds can beconverted into physiologically tolerable salts or prodrugs by standardprocesses known to those skilled in the art.

In one embodiment, the groups present in the compounds with the formulaXI can be modified by a variety of reactions and thus the desiredresidues R^(1′), R^(1″), R^(1′″) and R^(1″″) may be obtained. Forexample, nitro groups can be reduced to amino groups with variousreducing agents, such as sulphides, dithionites, and complex hydrides orby catalytic hydrogenation. A reduction of a nitro group may also becarried out at a later stage of the synthesis of a compound of theformula I, and a reduction of a nitro group to an amino group may alsooccur simultaneously with a reaction performed on another functionalgroup, for example when reacting a group like a cyano group withhydrogen sulphide or when hydrogenating a group. Ester groups present inthe benzene nucleus can be hydrolysed to the corresponding carboxylicacids, which after activation can then be reacted with amines oralcohols under standard conditions. Ether groups present at the benzenenucleus, for example benzyloxy groups or other easily cleavable ethergroups, can be cleaved to give hydroxyl groups that then can be reactedwith a variety of agents, for example etherification agents oractivating agents allowing replacement of the hydroxyl group by othergroups. Sulphur-containing groups can be reacted accordingly. In orderto introduce the residues attached to compounds of the formula XI, aminogroups can then be modified according to standard procedures foralkylation, for example by reaction with (substituted) alkyl halogenidesor by reductive amination of carbonyl compounds, according to standardprocedures for acylation, for example by reaction with activatedcarboxylic acid derivatives such as acid chlorides, anhydrides,activated esters or others or by reaction with carboxylic acids in thepresence of an activating agent, or according to standard procedures forsulfonylation, for example by reaction with sulfonyl chlorides. Halogensor hydroxyl groups, (via the triflate or nonaflate) primary amines (viaits diazonium salt), or boronic acid (after conversion to thecorresponding stannane), present in the structure of formula I can beconverted into a variety of other functional groups like for example—CN, —CF3, ethers, acids, amides, amines, alkyl- or aryl groups mediatedby means of transition metals, namely palladium or nickel catalysts orcopper salts and reagents referred in the literature cited below (F.Diederich, P. Stang, Metal-catalyzed Cross-coupling Reactions,Wiley-VCH, 1998; or M. Beller, C. Bolm, Transition Metals for OrganicSynthesis, Wiley-VCH, 1998; J. Tsuji, Palladium Reagents and Catalysts,Wiley, 1996; J. Hartwig, Angew. Chem. 110 (1998) 2154; B. Yang, S.Buchwald, J. Organomet. Chem. 576 (1999) 125; S. Wagaw, S. Buchwald J.Org. Chem. 61 (1996) 7240; J. Wolfe, S. Buchwald J. Org. Chem. 65 (2000)1144; D. Old, J. Wolfe, S. Buchwald J. Am. Chem. Soc. 120 (1998) 9722;J. Hartwig, M. Kawatsura, S. Hauck, K. Shaughnessy L. Alcazar-Roman, J.Org. Chem. 64 (1999) 5575, J. Wolfe, H. Tomori, J. Sadighi, J. Yin, S.Buchwald, J. Org. Chem. 65 (2000) 1158; T. Sakamoto, K. Ohsawa, J. Chem.Soc. Perkin Trans I, (1999) 2323; D. Nichols, S. Frescas, D.Marona-Lewicka, X. Huang, B. Roth, G. Gudelsky, J. Nash, J. Med. Chem,37 (1994) 4347; P. Lam, C. Clark, S. Saubern, J. Adams, M. Winters, D.Chan, A. Combs, Tetrahedron Lett., 39, (1998) 2941; D. Chan, K. Monaco,R. Wang, M. Winters, Tetrahedron Lett. 39, (1998) 2933; D. Su, J. Duan,Q. Chen, Tetrahedron Lett. 32 (1991) 7689; F. Qing, J. Fan, H. Sun, X.Yue, J. Chem. Perkin Trans. 1 (1997) 3053; V. Farina, V. Krishnamurthy,W. Scott, The Stille Reaction, Wiley, 1994)

To attach the groups R⁰—Q—X—Q′ to W in the formula XI, several standardmethods are known to those skilled in the art of organic synthesis (seee.g. J. March, Advanced Organic Chemistry, Fourth Edition, John Wiley &Sons, 1992). For example, the Mitsunobu reaction may be a usefulreaction (O. Mitsunobu, Synthesis 1981, 1), and further modifiedprocedures may also be used (A. Tunoori, D. Dutta, G. Gunda, TetrahedronLett. 39 (1998) 8751; J. Pelletier, S. Kincaid, Tetrahedron Lett. 41(2000) 797; D. L.Hughes, R. A. Reamer, J. J. Bergan, E. J. J. Grabowski,J. Am. Chem. Soc. 110 (1998) 6487; D. J. Camp, I. D. Jenkins, J. Org.Chem. 54 (1989) 3045; D. Crich, H. Dyker, R. J. Harris, J. Org. Chem. 54(1989) 257).

In order to make modifications during the course of the synthesis orprepare the groups R⁰—Q—X—Q′ or Y attached to the benzene nucleus byapplication of parallel synthesis methodology, beside a variety ofwell-known reactions, palladium catalysis may be used. Such reactionslike the Suzuki coupling, the Stille reaction, the Heck reaction, theSonogashira coupling or the Buchwald-Hartwig amination are well known bythose skilled in the art. (F. Diederich, P. Stang, Metal-catalyzedCross-coupling Reactions, Wiley-VCH, 1998; or M. Beller, C. Bolm,Transition Metals for Organic Synthesis, Wiley-VCH, 1998; J. Tsuji,Palladium Reagents and Catalysts, Wiley, 1996; J. Hartwig, Angew. Chem.110 (1998) 2154; B. Yang, S. Buchwald, J. Organomet. Chem. 576 (1999)125; J. Wolfe, S. Buchwald J. Org. Chem. 65 (2000) 1144; D. Old, J.Wolfe, S. Buchwald J. Am. Chem. Soc. 120 (1998) 9722; J. Hartwig, M.Kawatsura, S. Hauck, K. Shaughnessy L. Alcazar-Roman, J. Org. Chem. 64(1999) 5575, J. Wolfe, H. Tomori, J. Sadighi, J. Yin, S. Buchwald, J.Org. Chem. 65 (2000) 1185; P. Lam, C. Clark, S. Saubern, J. Adams, M.Winters, D. Chan, A. Combs, Tetrahedron Lett. 39 (1998) 2941; D. Chan,K. Monaco, R. Wang, M. Winters, Tetrahedron Lett. 39 (1998) 2933; J.Wolfe, H. Tomori, J. Sadight, J. Yin, S. Buchwald, J. Org. Chem. 65(2000) 1158; V. Farina, V. Krishnamurthy, W. Scott, The Stille Reaction,Wiley, 1994).

If the residue Y in a compound of the formula I contains a primary orsecondary nitrogen atom and is a residue in which functional groupswithin the residue Y are present in protected form or in the form of aprecursor group, which have not already been introduced during apreceding step, these residues can, for example, be introduced at thenitrogen position by conventional literature procedures well known toone skilled in the art for N-alkylation, reductive amination,N-arylation, N-acylation or N-sulfonylation of nitrogen atoms. Thestarting compound that is to be employed in such a reaction carries ahydrogen atom at the nitrogen position. N-Alkylation of a nitrogen atomcan, for example, be performed under standard conditions, which mayinclude the presence of a base, using an alkylating compound containinga leaving group for example halogen like chlorine, bromine or iodine, ora sulfonyloxy group like tosyloxy, mesyloxy ortrifluormethylsulfonyloxy. The leaving group may, for example, also be ahydroxyl group which, in order to achieve the alkylation reaction, isactivated by a conventional activating agent. For the preparation ofcompounds of the formula I in which G is a direct linkage and anaromatic group is directly bonded to the nitrogen atom in Y,conventional standard arylation procedures can be used. For example arylfluorides like alkyl fluorobenzoates or 4-fluorophenyl methyl sulfonescan be employed as arylating agents. Moreover, arylation of nitrogenwith heterocycles in compounds of the formula I is easily achieved bywell known standard substitution reactions of the correspondingheteroaryl chlorides or triflates. Alternatively a wide variety ofsubstituted aryl chlorides, aryl bromides, aryl iodides or aryltriflates can serve as arylating agents in a copper salt and/orpalladium mediated reaction according to R. Sarges, H. Howard, K. Koe,A. Weissmann, J. Med. Chem, 32 (1989) 437; P. Unangst, D. Connor, R.Stabler, R. Weikert, J. Heterocycl. Chem, 24 (1987) 811; G. Tokmakov, I.Grandberg, Tetrahedron, 51 (1995) 2091; D. Old, M. Harris, S. Buchwald,Org. Lett. 2 (2000) 1403, G. Mann, J. Hartwig, M. Driver, C.Fernandez-Rivas, J. Am. Chem. Soc. 120 (1998) 827; J. Hartwig, M.Kawatsura, S. Hauk, K. Shaughnessy, L. J. Org. Chem. 64 (1999) 5575.Moreover such arylations can also be accomplished by reaction of a widerange of substituted aryl boronic acids as demonstrated for example byW. Mederski, M. Lefort, M. Germann, D. Kux, Tetrahedron 55 (1999) 12757;P. Lam, C. Clark, S. Saubern, J. Adams, M. Winters, D. Chan, A. Combs,Tetrahedron Lett. 39 (1998) 2941; D. Chan, K. Monaco, R. Wang, M.Winters, Tetrahedron Lett. 39 (1998) 2933.

Other compounds of the formula I can be prepared in a similar fashion asdescribed above by coupling of a compound of the formula XIII with acompound of the formula XII.R⁰—Q—X—Q′—W—C(O)—Y  (XIII)in which R⁰, Q, Q′, X, W and Y are as defined above for the compounds ofthe formula I, but functional groups can optionally also be present inthe form of precursor groups or can be protected by protective groupsknown to those skilled in the art, e.g., an amino group can be protectedwith a tert-butyloxycarbonyl group or a benzyloxycarbonyl group or ahydroxyl group may be attached to a polystyrene resin.

The before-mentioned reactions for the conversion of functional groupsare furthermore in general extensively described in textbooks of organicchemistry like M. Smith, J. March, March's Advanced Organic Chemistry,Wiley-VCH, 2001 and in treatises like Houben-Weyl, “Methoden derOrganischen Chemie” (Methods of Organic Chemistry), Georg Thieme Verlag,Stuttgart, Germany, or “Organic Reactions”, John Wiley & Sons, New York,or R. C. Larock, “Comprehensive Organic Transformations”, Wiley-VCH, 2nded (1999), B. Trost, I. Fleming (eds.) Comprehensive Organic Synthesis,Pergamon, 1991, in which details on the reactions and primary sourceliterature can be found. Indeed, the compounds of the formula XI, XIIand XIII are prepared by methods well known to those skilled in the artby application of various standard procedures. Due to the fact that inthe present case the functional groups are attached to a highlyfunctionalized system, it may in certain cases become necessary tospecifically adapt reaction conditions or to choose specific reagentsfrom a variety of reagents that can in principle be employed into aconversion reaction, or otherwise to take specific measures forachieving a desired conversion, for example to use protection grouptechniques. However, finding out suitable reaction variants and reactionconditions in such cases does not cause any problems for one skilled inthe art.

Suitable methods include, but are not limited to, those described in theexamples.

The compounds of the present invention may be used as serine proteaseinhibitors, which inhibit the activity of the blood coagulation enzymesfactor Xa and/or factor VIIa. In one embodiment, they are highly activeinhibitors of factor Xa. They are generally specific serine proteaseinhibitors inasmuch as they do not substantially inhibit the activity ofother proteases whose inhibition is not desired. The activity of thecompounds of the formula I can be determined, for example, in the assaysdescribed below or in other assays known to those skilled in the art.With respect to factor Xa inhibition, one embodiment of the inventioncomprises compounds that have a Ki≦1 for factor Xa inhibition asdetermined in the assay described below, with or without concomitantfactor VIIa inhibition, and does not substantially inhibit the activityof other proteases involved in coagulation and fibrinolysis whoseinhibition is not desired (using the same concentration of theinhibitor). The compounds of the invention typically inhibit factor Xacatalytic activity either directly, within the prothrombinase complex oras a soluble subunit, or indirectly, by inhibiting the assembly offactor Xa into the prothrombinase complex.

The present invention also relates to the compounds of the formula I,and/or their physiologically tolerable salts, and/or their prodrugs foruse as pharmaceuticals (or medicaments), and to the use of any suchforms of the compounds for the production of pharmaceuticals useful forinhibiting factor Xa and/or factor VIIa, for influencing bloodcoagulation, inflammatory response or fibrinolysis, or for the therapyor prophylaxis of the diseases mentioned above or below. For example,the compounds may be used in pharmaceuticals for the therapy andprophylaxis of cardiovascular disorders, thromboembolic diseases orrestenoses. The invention also relates to the use of the compounds ofthe formula I and/or their physiologically tolerable salts and/or theirprodrugs for the inhibition of factor Xa and/or factor VIIa or forinfluencing blood coagulation or fibrinolysis or for the therapy orprophylaxis of the diseases mentioned above or below, for example foruse in the therapy and prophylaxis of cardiovascular disorders,thromboembolic diseases or restenoses, and to methods of treatmentaiming at such purposes including methods for said therapies andprophylaxis. The present invention also relates to pharmaceuticalpreparations (or pharmaceutical compositions) that contain an effectiveamount of at least one compound of the formula I and/or itsphysiologically tolerable salts and/or its prodrugs in addition to acustomary pharmaceutically acceptable carrier, i.e., one or morepharmaceutically acceptable carrier substances or excipients and/orauxiliary substances or additives.

In one embodiment, the compounds are used in the treatment of diseasestates such as abnormal thrombus formation, acute myocardial infarction,unstable angina, thromboembolism, acute vessel closure associated withthrombolytic therapy or percutaneous transluminal coronary angioplasty,transient ischemic attacks, stroke, pathologic thrombus formationoccurring in the veins of the lower extremities following abdominal,knee and hip surgery, a risk of pulmonary thromboembolism, ordisseminated systemic intravascular coagulatopathy occurring in vascularsystems during septic shock, certain viral infections or cancer.

The compounds of the formula I and their physiologically tolerable saltsand their prodrugs can be administered to animals, such as mammals, andin particular to humans as pharmaceuticals for therapy or prophylaxis.They can be administered on their own, or in mixtures with one anotheror in the form of pharmaceutical preparations, which permit enteral orparenteral administration.

The pharmaceuticals can be administered orally, for example in the formof pills, tablets, lacquered tablets, coated tablets, granules, hard andsoft gelatine capsules, solutions, syrups, emulsions, suspensions oraerosol mixtures. Administration, however, can also be carried outrectally, for example in the form of suppositories, or parentally, forexample intravenously, intramuscularly or subcutaneously, in the form ofinjection solutions or infusion solutions, microcapsules, implants orrods, or percutaneously or topically, for example in the form ofointments, solutions or tinctures, or in other ways, for example in theform of aerosols or nasal sprays.

The pharmaceutical preparations according to the invention are preparedin a manner known and familiar to one skilled in the art;pharmaceutically acceptable inert inorganic and/or organic carriers maybe used in addition to the compounds of the formula I and/or theirphysiologically tolerable salts and/or their prodrugs. For theproduction of pills, tablets, coated tablets and hard gelatine capsulesit is possible to use, for example, lactose, cornstarch or derivativesthereof, talc, stearic acid or its salts, etc. Carriers for soft gelatincapsules and suppositories include, for example, fats, waxes, semisolidand liquid polyols, natural or hardened oils, etc.

Suitable carriers for the production of solutions, such as injectionsolutions, emulsions, or syrups include, for example, water, saline,alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetableoils, etc. Suitable carriers for microcapsules, implants or rodsinclude, for example, copolymers of glycolic acid and lactic acid. Thepharmaceutical preparations normally contain about 0.5% to 90% by weightof the compounds of the formula I and/or their physiologically tolerablesalts and/or their prodrugs. The amount of the active ingredient of theformula I and/or its physiologically tolerable salts and/or its prodrugsin the pharmaceutical preparations normally is from about 0.5 mg toabout 1000 mg, In another embodiment, the active ingredient is presentfrom about 1 mg to about 500 mg.

In addition to the active ingredients of the formula I, and/or theirphysiologically acceptable salts, and/or prodrugs, and carriersubstances, the pharmaceutical preparations can contain additives suchas, for example, fillers, disintegrants, binders, lubricants, wettingagents, stabilisers, emulsifiers, preservatives, sweeteners, colorants,flavourings, aromatizers, thickeners, diluents, buffer substances,solvents, solubilizers, agents for achieving a depot effect, salts foraltering the osmotic pressure, coating agents or antioxidants. They canalso contain two or more compounds of the formula I, and/or theirphysiologically tolerable salts, and/or their prodrugs. In case apharmaceutical preparation contains two or more compounds of the formulaI, the selection of the individual compounds can aim at a specificoverall pharmacological profile of the pharmaceutical preparation. Forexample, a highly potent compound with a shorter duration of action maybe combined with a long-acting compound of lower potency. Theflexibility permitted with respect to the choice of substituents in thecompounds of the formula I allows a great deal of control over thebiological and physico-chemical properties of the compounds and thusallows the selection of such desired compounds. Furthermore, in additionto at least one compound of the formula I and/or its physiologicallytolerable salts and/or its prodrugs, the pharmaceutical preparations canalso contain one or more other therapeutically or prophylacticallyactive ingredients.

As inhibitors of factor Xa and/or factor VIIa, the compounds of theformula I, their physiologically tolerable salts, and their prodrugs aregenerally suitable for the therapy and prophylaxis of conditions inwhich the activity of factor Xa and/or factor VIIa plays a role or hasan undesired extent, or conditions that can favourably be influenced byinhibiting or decreasing the activity of factor Xa and/or factor VIIa.The compounds may be used in the prevention, alleviation or cure ofthese conditions by inhibiting or decreasing the activity of factor Xaand/or factor VIIa, as desired by a physician. As inhibition of factorXa and/or factor VIIa influences blood coagulation and fibrinolysis, thecompounds of the formula I and their physiologically tolerable salts andtheir prodrugs are generally suitable for reducing blood clotting, orfor the therapy and prophylaxis of conditions in which the activity ofthe blood coagulation system plays a role or has an undesired extent, orwhich can favourably be influenced by reducing blood clotting. Thecompounds may be used in, the prevention, alleviation or cure of theseconditions by decreasing activity of the blood coagulation system, asdesired by a physician. A specific subject of the present invention thusis the reduction or inhibition of unwanted blood clottingin anindividual by administering an effective amount of compound I, aphysiologically tolerable salt thereof, a prodrug thereof, or apharmaceutical preparation thereof.

Conditions in which a compound of the formula I can be favourably usedinclude, for example, cardiovascular disorders, thromboembolic diseasesor complications associated, for example, with infection or surgery. Thecompounds of the present invention can also be used to reduce aninflammatory response. Examples of specific disorders for the treatmentor prophylaxis of which the compounds of the formula I can be used arecoronary heart disease, myocardial infarction, angina pectoris, vascularrestenosis, for example restenosis following angioplasty like PTCA,adult respiratory distress syndrome, multi-organ failure, stroke anddisseminated intravascular clotting disorder. Examples of relatedcomplications associated with surgery are thromboses like deep vein andproximal vein thrombosis, which can occur following surgery. In view oftheir pharmacological activity, the compounds of the invention canreplace or supplement other anticoagulant agents such as heparin. Theuse of a compound of the invention can result, for example, in a costsaving as compared to other anticoagulants.

When using the compounds of the formula I the dose can vary within widelimits and, as is customary and is known to the physician, may be suitedto the individual conditions in each individual case. The dose maydepend, for example, on the specific compound employed, on the natureand severity of the disease to be treated, on the mode and the scheduleof administration, or on whether an acute or chronic condition istreated or whether prophylaxis is carried out. An appropriate dosage canbe established using clinical approaches well known in the medical art.In general, the daily dose for achieving the desired results in an adultweighing about 75 kg is from 0.01 mg/kg to 100 mg/kg. In anotherembodiment, from 0.1 mg/kg to 50 mg/kg or, from 0.1 mg/kg to 10 mg/kg(in each case in mg per kg of body weight) is used. The daily dose canbe dividedin the case of the administration of relatively large amounts,for example, into several parts for administration. As usual, dependingon individual behaviour, it may be necessary to deviate upwards ordownwards from the daily dose indicated.

A compound of the formula I can also advantageously be used as ananticoagulant outside an individual. For example, an effective amount ofa compound of the invention can be contacted with a freshly drawn bloodsample to prevent coagulation of the blood sample. Further, a compoundof the formula I and its salts can be used for diagnostic purposes, forexample for in vitro diagnoses, and as an auxiliary in biochemicalinvestigations. For example, a compound of the formula I can be used inan assay to identify the presence of factor Xa and/or factor VIIa, or toisolate factor Xa and/or factor VIIa, in a substantially purified form.A compound of the invention can be labelled with, for example, aradioisotope, and the labelled compound bound to factor Xa and/or factorVIIa is then detected using a routine method useful for detecting theparticular label. Thus, a compound of the formula I or a salt thereofcan be used as a probe to detect the location or amount of factor Xaand/or factor VIIa activity in vivo, in vitro, or ex vivo.

Furthermore, the compounds of the formula I can be used as synthesisintermediates for the preparation of other compounds, such as otherpharmaceutical active ingredients, which are obtainable from thecompounds of the formula I, for example, by introduction of substituentsor modification of functional groups.

The general synthetic sequences for preparing the compounds useful inthe present invention our outlined in the examples given below. Both anexplanation of, and the actual procedure for, the various aspects of thepresent invention are described where appropriate. The followingexamples are intended to be merely illustrative of the presentinvention, and not limiting thereof in either scope or spirit. Thosewith skill in the art will readily understand that known variations ofthe conditions and processes described in the examples can be used tosynthesise the compounds of the present invention.

It is understood that changes that do not substantially affect theactivity of the various embodiments of this invention are includedwithin the invention disclosed herein. Thus, the following examples areintended to illustrate but not limit the present invention.

EXAMPLES

Abbreviations Used:

tert-Butyl tBu 2,2′-bis(diphenylphoshino-1,1′-binaphthyl BinapBis-(oxo-3-oxazolidinyl)-phosphoryl chloride BOP-Cl dibenzylidenacetonedba Dichloromethane DCM Diethyl azodicarboxylate DEAD4-Dimethyaminopyridine DMAP N,N-Dimethylformamide DMF DimethylsulfoxideDMSO O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′- HATUtetramethyluronium-hexafluorophosphate N-Ethylmorpholine NEM MethanolMeOH Tetrahydrofuran THF Trifluoroacetic acid TFAO-((Ethoxycarbonyl)cyanomethyleneamino)- TOTUN,N,N′,N′-tetramethyluronium tetrafluoroborate

When in the final step of the synthesis of a compound an acid such astrifluoroacetic acid or acetic acid was used, the compound was obtainedpartially or completely in the form of a salt of the acid used. Forexample, when trifluoroacetic acid was employed to remove a tBu group orwhen a compound was purified by chromatography using an eluent thatcontained such an acid, in some cases (depending on the work-upprocedure such as, the particulars of a freeze-drying process), theresulting compound was obtained in the form of the acetic acid salt ortrifluoroacetic acid salt or hydrochloric acid salt.

Example 1{3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-phenyl}-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanone

0.100 g (0.29 mmol) of3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid was dissolvedin 2 ml of DMF and treated with 0.146 ml (1.16 mmol) of N-NEM and 51 mg(0.29 mmol) of 1-Pyridin-4-ylmethyl-piperazine and 0.098 g (0.3 mmol) ofTOTU. The solution was stirred for 1 h at RT. The solvent was removedunder reduced pressure, the residue was taken-up in DCM and the solutionwas washed three times with saturated aqueous sodium bicarbonate. Theorganic phase was dried with sodium sulphate, filtered and the solventwas removed under reduced pressure. The residue was chromatographed onsilica gel eluting with n-heptane/ethyl acetate (1/1), ethyl acetate,and ethyl acetate/MeOH (10/1).

Yield 102 mg. MS (ES⁺): m/e=500 (M⁺).

Example 2{3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-phenyl}-(4-pyridin-2-ylmethyl-piperazin-1-yl)-methanone

0.100 g (0.29 mmol) of3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid was dissolvedin 2 ml of DMF and treated with 0.146 ml (1.16 mmol) of N-NEM and 51 mg(0.29 mmol) of 1-Pyridin-2-ylmethyl-piperazine and 0.098 g (0.3 mmol) ofTOTU. The solution was stirred for 1 h at RT. The solvent was removedunder reduced pressure, the residue was taken-up in DCM and the solutionwas washed three times with saturated aqueous sodium bicarbonate. Theorganic phase was dried with sodium sulphate, filtered and the solventwas removed under reduced pressure. The residue was chromatographed onsilica gel eluting with n-heptane/ethyl acetate (1/1), ethyl acetate,and ethyl acetate/MeOH (10/1).

Yield 93 mg. MS (ES⁺): m/e=500 (M⁺).

Example 3{3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-phenyl}-(4-pyridin-4-yl-piperazin-1-yl)-methanone

0.100 g (0.29 mmol) of3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid was dissolvedin 2 ml of DMF and treated with 0.146 ml (1.16 mmol) of N-NEM and 47 mg(0.29 mmol) of 1-Pyridin-4-yl-piperazine and 0.098 g (0.3 mmol) of TOTU.The solution was stirred for 1 h at RT. The solvent was removed underreduced pressure, the residue was taken-up in DCM and the solution waswashed three times with saturated aqueous sodium bicarbonate. Theorganic phase was dried with sodium sulphate, filtered and the solventwas removed under reduced pressure. The residue was chromatographed onsilica gel eluting with n-heptane/ethyl acetate (1/1), ethyl acetate,and ethyl acetate/MeOH (10/1).

Yield 40 mg. MS (ES⁺): m/e=486 (M⁺).

Example 4{3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methyl-phenyl}-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanone

0.094 g (0.29 mmol) of3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methyl-benzoic acid was dissolvedin 2 ml of DMF and treated with 0.146 ml (1.16 mmol) of N-NEM and 51 mg(0.29 mmol) of 1-Pyridin-4-ylmethyl-piperazine and 0.098 g (0.3 mmol) ofTOTU. The solution was stirred for 16 h at RT. The solvent was removedunder reduced pressure, the residue was taken-up in DCM and the solutionwas washed three times with saturated aqueous sodium bicarbonate. Theorganic phase was dried with sodium sulphate, filtered and the solventwas removed under reduced pressure. The residue was chromatographed onsilica gel eluting with DCM, and DCM/MeOH (20/1).

Yield 82 mg. MS (ES⁺): m/e=484 (M⁺).

Example 5{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4,5-dimethoxy-phenyl}-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanone

(i) 3-Hydroxy-4,5-dimethoxy-benzoic acid methyl ester

5 g (27.2 mmol) of 3-Hydroxy-4,5-dimethoxy-benzoic acid was added at 0°C. to 100 ml of a saturated solution of HCl in MeOH. The solution wasstirred for 16 h at RT. The solvent was removed under reduced pressure.The residue was chromatographed on silica gel eluting with ethylacetate/n-heptane (2/1).

Yield 4.66 g. MS (Cl⁺): m/e=212.2 (M⁺).

(ii) 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4,5-dimethoxy-benzoic acid

2 g (9.42 mmol) of 3-Hydroxy-4,5-dimethoxy-benzoic acid methyl ester wasdissolved in 100 ml of anhydrous tetrahydrofuran. To this solution wasadded 1.98 g (10.37 mmol) of 2-(2,4-Dichlorophenyl)-ethanol, 9.415 g(equivalent to 28.27 mmol PPh₃) of triphenylphosphine derivatizedpolystyrene and 4.924 g (28.27 mmol) of DEAD. The solution was shakenfor 16 h at RT. The polymer was filtered off and washed with ethylacetate. The solvent was removed under reduced pressure. The residue wastaken-up in ethyl acetate and the solution was washed three times withwater and twice with saturated aqueous sodium chloride. The organicphase was dried with magnesium sulphate, filtered and the solvent wasremoved under reduced pressure.

The residue was dissolved in 20 ml of dioxan. 1 ml of water was added tothe solution followed by 2N aqueous NaOH to give a pH of 13. Thereaction solution was heated at 60° C. for 10 hours. The solution wascooled to 0° C., 5 ml water was added, followed by concentratedhydrochloric acid to give a pH of 1 to 2, whereupon the productprecipitated from solution. The product was filtered off and dried underreduced pressure.

Yield 3.3 g. MS (ES⁻): m/e=369 (M−H)⁻.

(iii){3-[2-(2,4-Dichlorophenyl)-ethoxy]-4,5-dimethoxy-phenyl}-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanone

0.100 g (0.269 mmol) of3-[2-(2,4-Dichlorophenyl)-ethoxy]-4,5-dimethoxy-benzoic acid wasdissolved in 2 ml of DMF and treated with 0.124 g (1.08 mmol) of N-NEMand 0.0477 g (0.27 mmol) of 1-Pyridin-4-ylmethyl-piperazine and 0.088 g(0.269 mmol) of TOTU. The solution was stirred for 16 h at RT. Thesolvent was removed under reduced pressure, the residue was taken-up inethyl acetate and the solution was washed twice with saturated aqueoussodium bicarbonate and once with saturated aqueous sodium chloride. Theorganic phase was dried with magnesium sulphate, filtered and thesolvent was removed under reduced pressure. The residue waschromatographed on silica gel eluting with a gradient of 0-17% MeOH inDCM.

Yield 23.8 mg. MS (ES⁺): m/e=530 (M⁺).

Example 63-[2-(2,4-Dichlorophenyl)-ethoxy]-4,5-dimethoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

0.100 g (0.269 mmol) of3-[2-(2,4-Dichlorophenyl)-ethoxy]-4,5-dimethoxy-benzoic acid wasdissolved in 2 ml of DMF and treated with 0.372 g (3.23 mmol) of N-NEMand 0.144 mg (0.27 mmol) ofC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetris-trifluoracetate salt and 0.088 g (0.269 mmol) of TOTU. The solutionwas stirred for 16 h at RT. The solvent was removed under reducedpressure, the residue was taken-up in ethyl acetate and the solution waswashed twice with saturated aqueous sodium bicarbonate and once withsaturated aqueous sodium chloride. The organic phase was dried withmagnesium sulphate, filtered and the solvent was removed under reducedpressure. The residue was chromatographed on silica gel eluting with agradient of 0-17% MeOH in DCM.

Yield 19.2 mg. MS (ES⁺): m/e=544 (M⁺).

Example 7{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-phenyl}-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanone

(i) 3-[2-(2,4-Dichlorophenyl)-ethoxy]-benzoic acid methyl ester

2 g (13.1 mmol) of 3-hydroxybenzoic acid methyl ester and 4.75 g (18.1mmol) of triphenylphosphine were dissolved in 48 ml of anhydroustetrahydrofuran. The solution was cooled to 0° C. and a solution of 3.04g (17.5 mmol) DEAD in 7 ml of anhydrous tetrahydrofuran was addeddropwise over 20 min. The solution was stirred at RT for 45 min. and asolution of 2.76 g (14.5 mmol) of 2-(2,4-Dichlorophenyl)-ethanol in 3 mlanhydrous tetrahydrofuran was added. The reaction was stirred for 16 hat RT. The solvent was removed under reduced pressure. The residue waschromatographed on silica gel eluting with ethyl acetate/n-heptane(4/1).

Yield 2.6 g. MS (Cl⁺): m/e=325 (M⁺).

(ii) 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-benzoic acid

1 g (3.07 mmol) of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-benzoic acid methylester was dissolved in 20 ml of dioxan. 2N aqueous NaOH was added to thesolution to give a pH of 13. The reaction solution was heated at 50° C.for 3 h, and stirred at RT for 16 h. 5 ml water was added, followed byconcentrated hydrochloric acid to give a pH of 1 to 2, whereupon theproduct precipitated from solution. The suspension was stirred for 30min, then the product was filtered off and dried under reduced pressure.

Yield 0.92 g. MS (Cl⁺): m/e=311 (M⁺).

(iii){3-[2-(2,4-Dichloro-phenyl)-ethoxy]-phenyl}-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanone

0.100 g (0.321 mmol) of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-benzoic acidwas dissolved in 2 ml of DMF and treated with 0.148 g (1.28 mmol) ofN-NEM and 0.105 g (0.321 mmol) of TOTU and 0.0569 g (0.32 mmol) of1-Pyridin-4-ylmethyl-piperazine. The solution was stirred for 16 h atRT. The solvent was removed under reduced pressure, the residue wastaken-up in ethyl acetate and the solution was washed twice withsaturated aqueous sodium bicarbonate and once with saturated aqueoussodium chloride. The organic phase was dried with magnesium sulphate,filtered and the solvent was removed under reduced pressure. The residuewas chromatographed on silica gel eluting with a gradient of 0-17% MeOHin DCM.

Yield 84 mg. MS (ES⁺): m/e=470 (M⁺).

Example 83-[2-(2,4-Dichlorophenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

0.100 g (0.321 mmol) of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-benzoic acidwas dissolved in 2 ml of DMF and treated with 0.148 g (1.28 mmol) ofN-NEM and 0.105 g (0.321 mmol) of TOTU and 0.123 g (0.64 mmol) ofC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylamine. Thesolution was stirred for 16 h at RT. The solvent was removed underreduced pressure, the residue was taken-up in ethyl acetate and thesolution was washed twice with saturated aqueous sodium bicarbonate andonce with saturated aqueous sodium chloride. The organic phase was driedwith magnesium sulphate, filtered and the solvent was removed underreduced pressure. The residue was chromatographed on silica gel elutingwith a gradient of 0 to 17% MeOH in DCM.

Yield 73 mg. MS (ES⁺): m/e=484 (M⁺).

Example 9{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-ethoxy-phenyl}-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanone

(i) 4-Ethoxy-3-hydroxy-benzoic acid ethyl ester

5 g (27.2 mmol) of 3,4-Dihydroxy-benzoic acid ethyl ester was dissolvedin 100 ml DMF and 3.75 g (27.2 mmol) of potassium carbonate was added.The solution was cooled to 0° C. and a solution of 2.96 g (27.2 mmol)ethyl bromide in 10 ml DMF was added dropwise. The solution was stirredfor 16 h at room temperature (RT). The solvent was removed under reducedpressure. The residue was taken-up in ethyl acetate and the solution waswashed three times with water and twice with saturated aqueous sodiumchloride. The organic phase was dried with magnesium sulphate, filteredand the solvent was removed under reduced pressure. The residue waschromatographed on silica gel eluting with ethyl acetate/n-heptane(1/4).

Yield 1.84 mg. MS (Cl⁺): m/e=211.1 (M+H)⁺.

(ii) 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-ethoxy-benzoic acid ethyl ester

0.5 g (2.38 mmol) of 4-Ethoxy-3-hydroxy-benzoic acid ethyl ester wasdissolved in 10 ml of anhydrous tetrahydrofuran. To this solution wasadded 0.5 g (2.62 mmol) of 2-(2,4-Dichlorophenyl)-ethanol, 2.38 g(equivalent to 7.13 mmol PPh₃) of triphenylphosphine derivatizedpolystyrene and 1.24 g (7.13 mmol) of DEAD. The solution was shaken for16 h at RT. The polymer was filtered off and washed with ethyl acetate.The solvent was removed under reduced pressure. The residue was taken-upin ethyl acetate and the solution was washed three times with water andtwice with saturated aqueous sodium chloride. The organic phase wasdried with magnesium sulphate, filtered and the solvent was removedunder reduced pressure. The residue was chromatographed on silica geleluting with ethyl acetate/n-heptane (1/4).

Yield 300 mg. LC-MS (ES⁺): m/e=383 (M)⁺.

(iii) 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-ethoxy-benzoic acid

0.300 g (0.78 mmol) of3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-ethoxy-benzoic acid ethyl ester wasdissolved in 10 ml of dioxan. 2N aqueous NaOH was added to the solutionto give a pH of 13. The reaction solution was heated at 60° C. for 10 h.5 ml water was added, followed by concentrated hydrochloric acid to givea pH of 1-2, whereupon the product precipitated from solution. Thesuspension was stirred for 30 min, and then the product was filtered offand dried under reduced pressure.

Yield 0.205 g. MS (ES⁺): m/e=355 (M⁺).

(iv){3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-ethoxy-phenyl}-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanone

0.050 g (0.141 mmol) of3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-ethoxy-benzoic acid was dissolvedin 2 ml of DMF and treated with 0.065 g (0.564 mmol) of N-NEM and 0.046g (0.141 mmol) of TOTU and 0.025 g (0.141 mmol) of1-Pyridin-4-ylmethyl-piperazine. The solution was stirred for 16 h atRT. The solvent was removed under reduced pressure, the residue wastaken-up in ethyl acetate and the solution was washed twice withsaturated aqueous sodium bicarbonate and once with saturated aqueoussodium chloride. The organic phase was dried with magnesium sulphate,filtered and the solvent was removed under reduced pressure. The residuewas purified by preparative RP-HPLC eluting with a gradient of 0-100%acetonitrile in water (+0.01% trifluoroacetic acid). Afterlyophilization the product was obtained as its trifluoroacetate salt.

Yield 28.6 mg. MS (ES⁺): m/e=514 (M⁺).

Example 103-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-ethoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

0.050 g (0.141 mmol) of3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-ethoxy-benzoic acid was dissolvedin 2 ml of DMF and treated with 0.163 g (1.41 mmol) of N-NEM and 0.046 g(0.141 mmol) of TOTU and 0.075 g (0.141 mmol) ofC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetris-trifluoroacetate salt. The solution was stirred for 16 h at RT. Thesolvent was removed under reduced pressure, the residue was taken-up inethyl acetate and the solution was washed twice with saturated aqueoussodium bicarbonate and once with saturated aqueous sodium chloride. Theorganic phase was dried with magnesium sulphate, filtered and thesolvent was removed under reduced pressure. The residue was purified bypreparative RP-HPLC eluting with a gradient of 0 to 100% acetonitrile inwater (+0.01% trifluoroacetic acid). After lyophilization the productwas obtained as its trifluoroacetate salt.

Yield 2.61 mg. MS (ES⁺): m/e=528 (M⁺).

Example 114-(4-{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoyl}-piperazin-1-ylmethyl)-benzonitrile

(i)4-{3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoyl}-piperazine-1-carboxylicacid tBu ester

3 g (9 mmol) of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoic acidwas dissolved in 30 ml DMF and treated with 4.6 ml (36 mmol) of N-NEMand 3.2 g (9.9 mmol) of TOTU and 1.67 g (9 mmol) ofpiperazine-1-carboxylic acid tBu ester. The solution was stirred for 40min. at RT. The solvent was removed under reduced pressure, the residuewas taken-up in DCM and the solution was washed three times withsaturated aqueous sodium bicarbonate. The organic phase was dried withsodium sulphate, filtered and the solvent was removed under reducedpressure. The residue was chromatographed on silica gel eluting withn-heptane/ethyl acetate (1/1).

Yield 4.2 g. MS (ES⁺): m/e=509 (M⁺).

(ii){3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-phenyl}-piperazin-1-yl-methanone,hydrochloride salt

4.2 g (8.2 mmol) of4-{3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoyl}-piperazine-1-carboxylicacid tBu ester was dissolved in 25 ml of MeOH. To this solution wasadded 100 ml of a saturated solution of HCl in MeOH. The solution wasstirred for 30 min at RT. The solvent was removed under reducedpressure. The residue was treated twice with toluene, which was removedunder reduced pressure.

Yield 3.8 g. MS (ES⁺): m/e=409 (M⁺).

(iii)4-(4-{3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoyl}-piperazin-1-ylmethyl)-benzonitrile

0.050 g (0.112 mmol) of{3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-phenyl}-piperazin-1-yl-methanone,hydrochloride salt was dissolved in 3 ml of DMF. 61.9 mg (0.448 mmol) ofpotassium carbonate was added to the solution, followed by 0.022 g (0.11mmol) of 4-bromomethyl-benzonitrile. The reaction solution was shakenfor 16 h at RT. The solvent was removed under reduced pressure, theresidue was taken-up in ethyl acetate and the solution was washed twicewith water and once with saturated aqueous sodium chloride. The organicphase was dried with magnesium sulphate, filtered and the solvent wasremoved under reduced pressure. The residue was chromatographed onsilica gel eluting with n-heptane/ethyl acetate (1/1), and DCM/MeOH(10/1).

Yield 33 mg. MS (ES⁺): m/e=524 (M⁺).

Example 12{3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-phenyl}-[4-(4-fluorobenzyl)-piperazin-1-yl]-methanone

0.050 g (0.112 mmol) of{3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-phenyl}-piperazin-1-yl-methanone,hydrochloride salt was dissolved in 3 ml of DMF. 61.9 mg (0.448 mmol) ofpotassium carbonate was added to the solution, followed by 0.021 g (0.11mmol) of 1-Bromomethyl-4-fluoro-benzene. The reaction solution wasshaken for 16 h at RT. The solvent was removed under reduced pressure,the residue was taken-up in ethyl acetate and the solution was washedtwice with water and once with saturated aqueous sodium chloride. Theorganic phase was dried with magnesium sulphate, filtered and thesolvent was removed under reduced pressure. The residue waschromatographed on silica gel eluting with n-heptane/ethyl acetate(1/1), and DCM/MeOH (10/1).

Yield 42.5 mg. MS (ES⁺): m/e=517 (M⁺).

Example 132-(4-{3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoyl}-piperazin-1-yl)-N,N-dimethyl-acetamide

0.050 g (0.112 mmol) of{3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-phenyl}-piperazin-1-yl-methanone,hydrochloride salt was dissolved in 3 ml of DMF. 61.9 mg (0.448 mmol) ofpotassium carbonate was added to the solution, followed by 0.016 g (0.13mmol) of 2-chloro-N,N-dimethyl-acetamide. The reaction solution wasshaken for 32 h at RT. The solvent was removed under reduced pressure.The residue was chromatographed on silica gel eluting with a gradient of0-17% MeOH in DCM, followed by additional purification by preparativeRP-HPLC eluting with a gradient of 0 to 100% acetonitrile in water(+0.01% trifluoroacetic acid). After lyophilization the product wasobtained as its trifluoroacetate salt.

Yield 20.5 mg. MS (ES⁺): m/e=494 (M⁺).

Example 142-(4-{3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoyl}-piperazin-1-yl)-1-pyrrolidin-1-yl-ethanone

0.102 g (0.3 mmol) of3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoic acid was dissolvedin 3 ml of DMF. 138.2 mg (1.2 mmol) of N-NEM and 0.098 g (0.3 mmol) TOTUwere added to the solution, followed by 0.059 g (0.3 mmol) of2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone. The reaction solution wasstirred for 4 h at RT. The solvent was removed under reduced pressure.The solvent was removed under reduced pressure, the residue was taken-upin ethyl acetate and the solution was washed three times with saturatedaqueous sodium bicarbonate. The organic phase was dried with sodiumsulphate, filtered and the solvent was removed under reduced pressure.The residue was purified by preparative RP-HPLC eluting with a gradientof 0-100% acetonitrile in water (+0.01% trifluoroacetic acid). Afterlyophilization the product was obtained as its trifluoroacetate salt.

Yield 74 mg. MS (ES⁺): m/e=520 (M⁺).

Example 153-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-N-(3-piperidin-1-yl-propyl)-benzamide

0.075 g (0.22 mmol) of3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoic acid was dissolvedin 3 ml of DMF. 101.3 mg (0.88 mmol) of N-NEM and 0.072 g (0.22 mmol)TOTU were added to the solution, followed by 0.031 g (0.22 mmol) of3-piperidin-1-yl-propylamine. The reaction solution was stirred for 4 hat RT. The solvent was removed under reduced pressure. The solvent wasremoved under reduced pressure, the residue was taken-up in ethylacetate and the solution was washed three times with saturated aqueoussodium bicarbonate. The organic phase was dried with sodium sulphate,filtered and the solvent was removed under reduced pressure. The residuewas purified by preparative RP-HPLC eluting with a gradient of 0-100%acetonitrile in water (+0.01% trifluoroacetic acid). Afterlyophilization the product was obtained as its trifluoroacetate salt.

Yield 50 mg. MS (ES⁺): m/e=465 (M⁺).

Example 163-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(2-piperidin-1-yl-ethyl)-benzamide

0.075 g (0.22 mmol) of3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoic acid was dissolvedin 3 ml of DMF. 101.3 mg (0.88 mmol) of N-NEM and 0.072 g (0.22 mmol)TOTU were added to the solution, followed by 0.028 g (0.22 mmol) of2-piperidin-1-yl-ethylamine. The reaction solution was stirred for 4 hat RT. The solvent was removed under reduced pressure. The solvent wasremoved under reduced pressure, the residue was taken-up in ethylacetate and the solution was washed three times with saturated aqueoussodium bicarbonate. The organic phase was dried with sodium sulphate,filtered and the solvent was removed under reduced pressure. The residuewas purified by preparative RP-HPLC eluting with a gradient of 0 to 100%acetonitrile in water (+0.01% trifluoroacetic acid). Afterlyophilization the product was obtained as its trifluoroacetate salt.

Yield 50 mg. MS (ES⁺): m/e=451 (M⁺).

Example 17{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-phenyl}-[4-(1-oxy-pyridin-4-ylmethyl)-piperazin-1-yl]-methanone

0.020 g (0.04 mmol) of{3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methyl-phenyl}-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanonewas dissolved in 1 ml of DCM. To this solution was added 15.2 mg (0.06mmol) meta-chloroperbenzoic acid. The reaction was stirred at RT for 16h, and then the solvent was removed under reduced pressure. The residuewas chromatographed on silica gel eluting with a gradient of 0 to 17%MeOH in DCM.

Yield 5 mg. MS (ES⁺): m/e=500 (M⁺).

Example 18{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-hydroxymethyl-phenyl}-[4-(1-oxy-pyridin-4-ylmethyl)-piperazin-1-yl]-methanone

This compound was isolated by chromatography from the reaction describedfor the synthesis of example 17. Yield 2 mg. MS (ES⁺): m/e=516 (M⁺).

Example 19{4-Bromo-3-[2-(2,4-Dichlorophenyl)-ethoxy]-5-methoxyphenyl}-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanone

(i) 4-Bromo-3-[2-(2,4-Dichlorophenyl)-ethoxy]-5-methoxy-benzoic acid

0.2 g (0.49 mmol) of4-Bromo-3-[2-(2,4-dichlorophenyl)-ethoxy]-5-hydroxy-benzoic acid wasdissolved in 5 ml DMF and 0.272 mg (1.97 mmol) of potassium carbonatewas added. The solution was cooled to 0° C. and 0.699 g (4.9 mmol)methyl bromide was added. The solution was stirred for 16 h at RT. Thesolvent was removed under reduced pressure. The residue waschromatographed on silica gel eluting with ethyl acetate/n-heptane(1/1). The resulting compound was dissolved in 10 ml dioxan and 1 mlwater. 2N aqueous NaOH was added to the solution to give a pH of 13. Thereaction solution was heated at 60° C. for 4 h. 5 ml water was added,followed by concentrated hydrochloric acid to give a pH of 1-2,whereupon the product precipitated from solution. The suspension wasstirred for 30 min, then the product was filtered off and dried underreduced pressure.

Yield 120 mg. MS (ES⁻): m/e=500 (M−H)⁻.

(ii){4-Bromo-3-[2-(2,4-dichlorophenyl)-ethoxy]-5-methoxyphenyl}-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanone

0.05 g (0.119 mmol) of4-Bromo-3-[2-(2,4-dichlorophenyl)-ethoxy]-5-methoxy-benzoic acid wasdissolved in 2 ml of DMF and treated with 0.055 g (0.476 mmol) of N-NEMand 0.039 g (0.119 mmol) of TOTU and 0.021 g (0.12 mmol) of1-Pyridin-4-ylmethyl-piperazine. The solution was stirred for 16 h atRT. The solvent was removed under reduced pressure, the residue wastaken-up in acetonitrile and the residue was purified by preparativeRP-HPLC eluting with a gradient of 0 to 100% acetonitrile in water(+0.01% trifluoroacetic acid). After lyophilization the product wasobtained as its trifluoroacetate salt.

Yield 35.5 mg. MS (ES⁺): m/e=578 (M+H)⁺.

Example 204-Bromo-3-[2-(2,4-Dichloro-phenyl)-ethoxy]-5-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

0.05 g (0.119 mmol) of4-Bromo-3-[2-(2,4-dichlorophenyl)-ethoxy]-5-methoxy-benzoic acid wasdissolved in 2 ml of DMF and treated with 0.055 g (0.476 mmol) of N-NEMand 0.039 g (0.119 mmol) of TOTU and 0.063 g (0.12 mmol) ofC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetris-trifluoroacetate salt. The solution was stirred for 16 h at RT. Thesolvent was removed under reduced pressure, the residue was taken-up inacetonitrile and the residue was purified by preparative RP-HPLC elutingwith a gradient of 0 to 100% acetonitrile in water (+0.01%trifluoroacetic acid). After lyophilization the product was obtained asits trifluoroacetate salt.

Yield 34.3 mg. MS (ES⁺): m/e=592 (M+H)⁺.

Example 213-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(2′-sulfamoyl-biphenyl-4-ylmethyl)-benzamide

(i) 4′-Aminomethyl-biphenyl-2-sulfonic acid dimethylaminomethyleneamide

1.5 g of 4′-formyl-biphenyl-2-sulfonic acid dimethylaminomethyleneamideprepared according to H. Jendralla et al. (Liebigs Ann. 1995, 1253-7) in15 ml MeOH were treated with 208.6 mg NaCNBH₃ and the reaction wasstirred for 4 hours at RT. The pH was adjusted to 4.0, the reaction wasfiltered, the solvent was removed under reduced pressure and the residuewas chromatographed on silica gel eluting with a gradient of 10-20% MeOHin DCM.

Yield 912 mg. MS (ES⁺): m/e=318 (M+H)⁺.

(ii) 4′-Aminomethyl-biphenyl-2-sulfonic acid amide hydrochloride

400 mg of 4′-Aminomethyl-biphenyl-2-sulfonic aciddimethylaminomethyleneamide were treated with 10 ml MeOH and 4 ml conc.HCl and refluxed for 1 h. Solvent and HCl were evaporated and theproduct used without purification.

(iii)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(2′-sulfamoyl-biphenyl-4-ylmethyl)-benzamide

77 mg of 4′-aminomethyl-biphenyl-2-sulfonic acid amide hydrochloridewere reacted with 100 mg of3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid, 111 mg HATUand 0.2 ml DIPEA in 3 ml DMF for 1 h at RT. The pH was adjusted to 4.0,the solvent evaporated, the residue was dissolved in DCM and extractedwith brine. After evaporation of the solvent, the product was purifiedby preparative RP-HPLC eluting with a gradient of 0-100% acetonitrile inwater (+0.01% trifluoroacetic acid). After lyophilisation the productwas obtained as its trifluoroacetate salt.

Yield: 33 mg. MS (ES⁺): m/e=585.1; 587.0 (M+H⁺).

Example 223-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-benzamide

(i) 3-Hydroxy-4-methoxy-benzoic acid methyl ester

10 ml of thionyl chloride was added to 250 ml of MeOH at 0° C. Thesolution was stirred for 10 min. and 25 g of 3-hydroxy-4-methoxybenzoicacid was added. The reaction was stirred for 16 h at RT then heated to50° C. for 3 h. The solvents were removed under reduced pressure. Theresidue was directly used in the next reaction.

(ii) 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoic acid methylester

20 g of triphenylphosphine and 10 g of 3-Hydroxy-4-methoxy-benzoic acidmethyl ester were dissolved in 200 ml of anhydrous THF. The solution wascooled to 0° C. to 10° C. and a solution of 11.4 ml DEAD in 30 mlanhydrous THF was added dropwise over 20 min. The reaction was warmed toRT and stirred for 45 min. A solution of 11.3 ml2-(2,4-Dichlorophenyl)-ethanol in 10 ml anhydrous THF was added withcooling. The reaction was stirred at RT for 16 h, and then the solventswere removed under reduced pressure. The residue was treated withn-heptane:ethyl acetate/1:1. The filtrate was dried under reducedpressure. The product was purified by silica gel chromatography, elutingwith n-heptane:ethyl acetate/4:1, then n-heptane:ethyl acetate/3:1.

Yield 17 g.

(iii) 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoic acid

17 g of 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4-methoxy-benzoic acid methylester were dissolved in 200 ml of MeOH:water/3:1. 4.1 g of lithiumhydroxide monohydrate was added to the solution, and the reaction wasstirred at RT for 16 h then at 90° C. for 2 h. The solution was cooledto RT, then acidified with half-concentrated hydrochloric acid. Thesolvents were removed under reduced pressure and the residue was washedtwice with warm water to remove salts. The so obtained acid was used forthe subsequent reaction without further purification.

(iv)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-benzamide

To a solution of 100 mg3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid in 1 ml DMF 53mg carbonyldiimidazole were added. After stirring for 2 h at RT 48 mg ofC-(1H-Pyrrolo[3,2-c]pyridin-2-yl)-methylamine tris-trifluoroacetate[prepared by adopting a procedure described by F. Ujjainwalla, D.Warner; Tertrahedron Lett. 1998, 39, 5355 and L. Xu, I. Lewis, S.Davidsen, J. Summers, Tertrahedron Lett. 1998, 39, 5159] were added andstirred over night after addition of 5 mg of DMAP. The solvent wasremoved under reduced pressure and the residue purified by preparativeHPLC (C₁₈ reverse phase column, elution with a H₂O/MeCN gradient with0.5% TFA) The fractions containing the product were evaporated andlyophilised. The product was obtained as its trifluoroacetate salt.

Yield 48 mg. MS (ESI+): m/e=470, chloro pattern

Example 233-[2-(2,4-Dichloro-phenyl)-ethoxy]-N-furo[3,2-c]pyridin-2-ylmethyl-4-methoxy-benzamide

The title compound was prepared analogously to Example 22 with thedifference that C-Furo[3,2-c]pyridin-2-yl-methylamine [prepared byadopting a procedure described by F. Ujjainwalla, D. Warner;Tertrahedron Lett. 1998, 39, 5355 and L. Xu, I. Lewis, S. Davidsen, J.Summers, Tertrahedron Lett. 1998, 39, 5159] was used instead ofC-(1H-Pyrrolo[3,2-c]pyridin-2-yl)-methylamine. MS (ESI+): 471, chloropattern

Example 243-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(3-pyridin-4-yl-4,5-dihydro-isoxazol-5-ylmethyl)-benzamide

The title compound was prepared analogously to Example 22 with thedifference that C-(3-Pyridin-4-yl-4,5-dihydro-isoxazol-5-yl)-methylaminewas used instead of C-(1H-Pyrrolo[3,2-c]pyridin-2-yl)-methylamine. MS(ESI+): 500, chloro pattern

Example 253-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(2-pyridin-4-yl-ethyl)-benzamide

The title compound was prepared analogously to Example 22 with thedifference that 2-Pyridin-4-yl-ethylamine was used instead ofC-(1H-Pyrrolo[3,2-c]pyridin-2-yl)-methylamine. MS (ESI+): 445, chloropattern

Example 263-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(2-pyridin-2-yl-ethyl)-benzamide

The title compound was prepared analogously to Example 22 with thedifference that 2-Pyridin-2-yl-ethylamine was used instead ofC-(1H-Pyrrolo[3,2-c]pyridin-2-yl)-methylamine. MS (ESI+): 445, chloropattern

Example 273-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamide

To a solution of 3 g3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid in 20 mlCH₂Cl₂ 4.5 ml N-NEM and subsequently 2.9 g TOTU were added. Afterstirring for 1 h at RT 2.8 g 4-Aminomethyl-piperidine-1-carboxylic acidtBu ester in 10 ml CH₂Cl₂ were added and the mixture was stirred for 2h. The reaction mixture was then diluted with 50 ml CH₂Cl₂ and waswashed with saturated aqueous NaHCO₃ solution. The organic layer wasdried over Na₂SO₄. After removal of the solvent the white residue wasrecrystallized from ethyl acetate to yield 4.8 g of the BOC-protectedderivative. This crystalline white solid was suspended in EtOH/HCl atRT. After 3 h a clear solution was obtained. Removal of the solventunder reduced pressure yielded a white foam.

Yield: 3.7 g MS (ESI+): 437, chloro pattern

Alternatively the compound could be obtained by activation withcarbonylimidazole and subsequent reaction of the activated intermediatewith C-Piperidin-4-yl-methylamine.

Example 283-[2-(2,4-Dichloro-phenyl)-ethoxy]-N-[3-(1-hydroxy-pyridin-4-yl)-4,5-dihydro-isoxazol-5-ylmethyl]-4-methoxy-benzamide

To a solution of 100 mg3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(3-pyridin-4-yl-4,5-dihydro-isoxazol-5-ylmethyl)-benzamidein 5 ml CH₂Cl₂ 70 mg MCPBA were added at RT and stirred over night. Thesolvent was removed under reduced pressure and the residue purified bypreparative HPLC (C₁₈ reverse phase column, elution with a H₂O/MeCNgradient with 0.5% TFA) The fractions containing the product wereevaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 50 mg MS (ESI+): 516, chloro pattern

Example 293-[2-(2,4-Dichloro-phenyl)-ethoxy]-N-[3-(1-methyl-pyridin-4-ium)-4,5-dihydro-isoxazol-5-ylmethyl]-4-methoxy-benzamidyliodide

To a solution 30 mg (0.06 mmol)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(3-pyridin-4-yl-4,5-dihydro-isoxazol-5-ylmethyl)-benzamidein 5 ml acetone 0.3 ml Mel were added at RT and stirred for 2 d. Theproduct precipitated from the solution as a yellow solid that wasisolated by filtration.

Yield. 25 mg MS (ESI+): 515, chloro pattern

Example 30N-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methoxy-benzamide

To a solution of 250 mg hexamethylenetetraamine (1.8 mmol) in 8 ml CHCl₃500 mg (1.8 mmol) 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole[Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls,Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney,Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li,Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl.(2001), 460 pp. WO 0107436 A2]. was added and the reaction mixturestirred at 50° C. for 1 h and kept for additional 3 h at RT. The solventwas removed under reduced pressure and the residue was taken up in 5 mlEtOH and 2 ml concentrated HCl. This solution was heated for 5 h at 50°C. and the precipitate collected by filtration. An aliquot (68 mg) ofthe obtained amine was then subsequently coupled with 100 mg (0.29 mmol)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid preactivatedby addition of 95 mg TOTU and 150 mg N-NEM in 2 ml CH₂Cl₂. Afterstirring over night at RT the solvent was removed under reduced pressurean taken up in 3 ml saturated NaHCO₃ solution and filtered through achem elut® cartridge by elution with ethyl acetate. After concentrationunder reduced pressure and purification by preparative HPLC (C₁₈ reversephase column, elution with a H₂O/MeCN gradient with 0.5% TFA) thefractions containing the product were evaporated and lyophilised. Theproduct was obtained as its trifluoroacetate salt. Yield 10 mg

MS (ESI+): 537, chloro pattern

Example 31N-(4-Aminomethyl-cyclohexylmethyl)-3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methoxy-benzamide

To a solution of 100 mg3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid in 2 ml CH₂Cl₂150 μl N-NEM and subsequently 96 mg TOTU were added. After stirring for1 h at room temperature (RT) 83 mgC-(4-Aminomethyl-cyclohexyl)-methylamine in 1 ml CH₂Cl₂ were added andthe mixture was stirred for additional 2 h followed by removal of thesolvent under reduced pressure. The residue was taken up in 3 mlsaturated NaHCO₃ solution and filtered through a chem elut® cartridge byelution with ethyl acetate. After concentration under reduced pressureand purification by preparative HPLC (C₁₈ reverse phase column, elutionwith a H₂O/MeCN gradient with 0.5% TFA) the fractions containing theproduct were evaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 32 mg MS (ESI+): 465, chloro pattern

Example 323-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(1-pyridin-4-ylmethyl-piperidin-4-ylmethyl)-benzamide

A suspension of 120 mg3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamide,50 mg 4-Picolylchloride hydrochloride and 110 mg Cs₂CO₃ in 2 ml DMF wasstirred at RT over night. The reaction mixture was diluted with 2 mlwater, filtered through a chem elut® cartridge by elution with ethylacetate. After concentration under reduced pressure and purification bypreparative HPLC (C18 reverse phase column, elution with a H₂O/MeCNgradient with 0.5% TFA) the fractions containing the product wereevaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 22 mg MS (ESI+): 528, chloro pattern

Analogously to example 32 the following compounds were prepared by asimilar procedure

Example Structure MS (ESI+) 33

527, chloro pattern 34

544, chloro pattern 35

578, chloro pattern 36

552, chloro pattern 37

527, chloro pattern 38

595, chloro pattern

Example 393-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(1-methyl-1H-benzoimidazol-5-yl)-benzamide

This compound was prepared analogously to example 31 employing1-Methyl-1H-benzoimidazol-5-ylamine as amine component. MS (ESI+): 470,chloro pattern

Example 403-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-[4-(pyrimidin-2-ylsulfamoyl)-phenyl]-benzamide

To a solution of 100 mg3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid in 2 ml CH₂Cl₂150 μl TEA and subsequently 77 mg TFFH were added. After stirring for 1h at RT 87 mg 4-Amino-N-pyrimidin-2-yl-benzenesulfonamide in 1 ml CH₂Cl₂were added and the mixture was stirred over night followed by removal ofthe solvent under reduced pressure. The residue was taken up in 3 mlsaturated NaHCO₃ solution and filtered through a chem elut® cartridge byelution with ethyl acetate. After concentration under reduced pressureand purification by preparative HPLC (C18 reverse phase column, elutionwith a H₂O/MeCN gradient with 0.5% TFA) the fractions containing theproduct were evaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 11 mg MS (ESI+): 573, chloro pattern

Example 41N-[1-(5-Chloro-thiophene-2-sulfonyl)-piperidin-4-ylmethyl]-3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methoxy-benzamide

To a solution of 50 mg (0.14 mmol)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamideand 200 μl TEA in 3 ml DMF/CH₂Cl₂ 1:2, 73 mg5-Chloro-thiophene-2-sulfonyl chloride were added at RT. The reactionmixture was stirred over night followed by concentration under reducedpressure. The residue was taken up in 1 ml (0.5M) NaOH solution andfiltered through a chem elut® cartridge by elution with ethyl acetate.After concentration under reduced pressure and purification bypreparative HPLC (C₁₈ reverse phase column, elution with a H₂O/MeCNgradient with 0.5% TFA) the fractions containing the product wereevaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 15 mg MS (ESI+): 617, chloro pattern

Analogously to example 42 the following compounds were prepared by asimilar procedure:

Example Structure MS (ESI+) 43

583, chloro pattern 44

624, chloro pattern 45

602, chloro pattern 46

581, chloro pattern 47

602, chloro pattern

Example 483-[2-(2,4-Dichloro-phenyl)-ethoxy]-N-[1-(4-dimethylamino-benzoyl)-piperidin-4-ylmethyl]-4-methoxy-benzamide

To a solution of 50 mg (0.14 mmol)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamideand 200 μl TEA in 3 ml DMF/CH₂Cl₂ 1:2, 61 mg 4-Dimethylamino-benzoylchloride hydrochloride were added at RT. The reaction mixture wasstirred over night followed by concentration under reduced pressure. Theresidue was taken up in 1 ml (0.5M) NaOH solution and filtered through achem elut® cartridge by elution with ethyl acetate. After concentrationunder reduced pressure and purification by preparative HPLC (C18 reversephase column, elution with a H₂O/MeCN gradient with 0.5% TFA) thefractions containing the product were evaporated and lyophilised. Theproduct was obtained as its trifluoroacetate salt.

Yield: 10 mg MS (ESI+): 584, chloro pattern

Example 49N-[1-(2-Chloro-pyridine-4-carbonyl)-piperidin-4-ylmethyl]-3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methoxy-benzamide

The title compound was prepared analogously to example 48 employing2-Chloro-isonicotinoyl chloride hydrochloride as acylation component.

MS (ESI+): 576, chloro pattern

Example 503-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-[1-(pyridine-3-carbonyl)-piperidin-4-ylmethyl]-benzamide

The title compound was prepared analogously to example 48 employingNicotinoyl chloride hydrochloride as acylation component. MS (ESI+):542, chloro pattern

Example 513-[2-(2,4-Dichloro-phenyl)-ethoxy]-N-[1-(2,2-dimethyl-propionyl)-piperidin-4-ylmethyl]-4-methoxy-benzamide

This compound was prepared analogously to example 48 employing pivalicanhydride as acylation component. MS (ESI+): 521, chloro pattern

Example 523-[2-(2,4-Dichloro-phenyl)-ethoxy]-N-[1-(6-hydroxy-pyridine-3-carbonyl)-piperidin-4-ylmethyl]-4-methoxy-benzamide

To a solution of 100 mg3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamidein 2 ml CH₂Cl₂ 150 μl N-NEM and subsequently 150 mg TOTU were added.After stirring for 1 h at RT 70 mg 6-Hydroxy-nicotinic acid in 1 mlCH₂Cl₂ were added and the mixture was stirred for additional 2 hfollowed by removal of the solvent under reduced pressure. The residuewas taken up in 3 ml saturated NaHCO₃ solution and filtered through achem elut® cartridge by elution with ethyl acetate. After concentrationunder reduced pressure and purification by preparative HPLC (C₁₈ reversephase column, elution with a H₂O/MeCN gradient with 0.5% TFA) thefractions containing the product were evaporated and lyophilised. Theproduct was obtained as its trifluoroacetate salt.

Yield: 45 mg MS (ESI+): 558, chloro pattern

Example 533-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-[1-(2-methoxy-pyridine-3-carbonyl)-piperidin-4-ylmethyl]-benzamide

The title compound was prepared analogously to example 52 employing2-Methoxy-nicotinic acid as acylation component MS (ESI+): 572, chloropattern

Example 54N-(1-Cyclopentyl-piperidin-4-ylmethyl)-3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methoxy-benzamide

To a solution of 100 mg3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamideand 35 mg cyclopentanone in 2 ml acetonitrile 27 mg Na(CN)BH₃ wereintroduced. After stirring at RT overnight the reaction mixture washeated to 80° C. for 4 h. After removal of the solvent under reducedpressure and purification by preparative HPLC (C₁₈ reverse phase column,elution with a H₂O/MeCN gradient with 0.5% TFA) the fractions containingthe product were evaporated and lyophilised. The product was obtained asits trifluoroacetate salt.

Yield: 47 g MS (ESI+): 505, chloro pattern

Analogously to example 54 the following compounds were prepared by asimilar procedure:

Example Structure MS (ESI+) 55

479, chloro pattern 56

519, chloro pattern 57

533, chloro pattern 58

577, chloro pattern 59

520, chloro pattern 60

521, chloro pattern

Example 613-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(2′-methyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

A solution of 100 mg3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamideand 60 mg 4-Chloro-2-picoline in 6 ml n-BuOH/NEt₃ 5:1 was refluxedovernight. After subsequent removal of the solvent under reducedpressure and purification by preparative HPLC (C₁₈ reverse phase column,elution with a H₂O/MeCN gradient with 0.5% TFA) the fractions containingthe product were evaporated and lyophilised. The product was obtained asits trifluoroacetate salt.

Yield: 67 mg MS (ESI+): 528, chloro pattern

Analogously to example 61 the following compounds were prepared by asimilar procedure:

Example Structure MS (ESI+) 62

515, chloro pattern 63

544, chloro pattern 64

561, chloro pattern 65

575, chloro pattern 66

530, chloro pattern

Example 673-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

A mixture of 110 mg (0.25 mmol)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamide,49 mg (0.49 mmol) 4-Bromopyridine hydrochloride, 57 mg sodium-t-butoxidein 5 ml THF were purged with argon for 10 min. Then 15 mg of (+)-R-Binapand 15 mg Pd(OAc)₂ were added under argon and the mixture refluxedovernight. The residue was taken up in 3 ml saturated NaHCO₃ solutionand filtered through a chem elut® cartridge by elution with ethylacetate. Subsequent removal of the solvent under reduced pressure andpurification by preparative HPLC (C₁₈ reverse phase column, elution witha H₂O/MeCN gradient with 0.5% TFA) the fractions containing the productwere evaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 35 mg MS (ESI+): 514, chloro pattern

Example 683-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl)-benzamide

This compound was prepared analogously to example 67 employing2-Bromopyridine hydrochloride coupling component. MS (ESI+): 514, chloropattern

Example 69N-[1-(4-Chloro-phenyl)-piperidin-4-ylmethyl]-3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methoxy-benzamide

A mixture of 100 mg (0.2 mmol)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamide,66 mg (0.34 mmol) 4-Bromochlorobenzene, 33 mg sodium-t-butoxide in 5 mlTHF were purged with argon for 10 min. Then 37 mg of dppf and 5 mgPd(OAc)₂ were added under argon and the mixture refluxed overnight. Theresidue was taken up in 3 ml saturated NaHCO₃ solution and filteredthrough a chem elut® cartridge by elution with ethyl acetate. Subsequentremoval of the solvent under reduced pressure and purification bypreparative HPLC (C18 reverse phase column, elution with a H₂O/MeCNgradient with 0.5% TFA) the fractions containing the product wereevaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 47 mg MS (ESI+): 547, chloro pattern

Analogously to example 69 the following compounds were prepared by asimilar procedure:

Example Structure MS (ESI+) 70

538, chloro pattern 71

591, chloro pattern 72

585, chloro pattern 73

544, chloro pattern

Example 743-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(1-pyrimidin-5-yl-piperidin-4-ylmethyl)-benzamide

A mixture of 100 mg (0.2 mmol)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamide,50 mg (0.32 mmol) 4-Brompyrimidine, 70 mg sodium-t-butoxide in 5 mldioxane were purged with argon for 10 min. Then 37 mg of2-(Dicyclohexylphosphino)biphenyl and 20 mg Pd₂(dba)₃ were added underargon and the mixture refluxed overnight. The residue was taken up in 3ml saturated NaHCO₃ solution and filtered through a chem elut® cartridgeby elution with ethyl acetate. Subsequent removal of the solvent underreduced pressure and purification by preparative HPLC (C₁₈ reverse phasecolumn, elution with a H₂O/MeCN gradient with 0.5% TFA) the fractionscontaining the product were evaporated and lyophilised. The product wasobtained as its trifluoroacetate salt.

Yield: 21 mg MS (ESI+): 515, chloro pattern

Example 753-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(6′-methoxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-ylmethyl)-benzamide

A mixture of 100 mg (0.2 mmol)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamide,55 mg (0.32 mmol) 5-Brom-2-methoxypyridine, 70 mg sodium-t-butoxide in 5ml dioxane were purged with argon for 10 min. Then 37 mg of2-(Dicyclohexylphosphino)biphenyl and 20 mg Pd₂(dba)₃ were added underargon and the mixture refluxed overnight. The residue was taken up in 3ml saturated NaHCO₃ solution and filtered through a chem elut® cartridgeby elution with ethyl acetate. Subsequent removal of the solvent underreduced pressure and purification by preparative HPLC (C₁₈ reverse phasecolumn, elution with a H₂O/MeCN gradient with 0.5% TFA) the fractionscontaining the product were evaporated and lyophilised. The product wasobtained as its trifluoroacetate salt.

Yield: 52 mg MS (ESI+): 544, chloro pattern

Example 763-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(1-phenyl-piperidin-4-ylmethyl)-benzamide

A mixture of 100 mg (0.2 mmol)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamide,50 mg (0.32 mmol) Bromobenzene, 70 mg sodium-t-butoxide in 5 ml dioxanewere purged with argon for 10 min. Then 37 mg of2-(Dicyclohexylphosphino)biphenyl and 20 mg Pd₂(dba)₃ were added underargon and the mixture refluxed overnight. The residue was taken up in 3ml saturated NaHCO₃ solution and filtered through a chem elut® cartridgeby elution with ethyl acetate. Subsequent removal of the solvent underreduced pressure and purification by preparative HPLC (C18 reverse phasecolumn, elution with a H₂O/MeCN gradient with 0.5% TFA) the fractionscontaining the product were evaporated and lyophilised.

Yield: 14 mg MS (ESI+): 513, chloro pattern

Example 774-Bromo-3-[2-(2,4-dichloro-phenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-carbamic acid tBuester

A suspension of 5 g (23.3 mmol) piperidin-4-ylmethyl-carbamic acid tBuester 3.85 g (25.7 mmol) 4-chloropyridin hydrochloride in 15 mln-BuOH/H₂O/NEt₃ 1:1:1 was refluxed for 3 days. After removal of thesolvent under reduced pressure the residue was purified bychromatography on silica with CH₂Cl₂/MeOH 100:1→50:1→10:1-5:1 to yield awhite solid.(ii) C-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-Yl)-methylamine tristrifluoroacetate

To a solution of 4.58 g(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-carbamic acid tBuester in 12 ml CH₂Cl₂12 ml TFA were added at RT. After stirring for 30min the solution was diluted with 20 ml of toluene and evaporated underreduced pressure. The residue was codestilled twice with toluene andthen used in the subsequent reactions without further purification.

(iii) 4-Bromo-3-hydroxy-benzoic acid methyl ester

1.5 ml of thionyl chloride was added to 40 ml of MeOH at 0° C. Thesolution was stirred for 10 min and 5 g of 4-Bromo-3-hydroxy-benzoicacid was added. The reaction was stirred for 16 h at RT then heated to50° C. for 3 h. The solvents were removed under reduced pressure. Theresidue was used directly in the next step. Yield 5.92 g

(iv) 4-Bromo-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid methylester

1.6 g of triphenylphosphine and 1 g of 4-Bromo-3-hydroxy-benzoic acidmethyl ester were dissolved in 15 ml of anhydrous THF. The solution wascooled to 0° C. to 10° C. and a solution of 0.88 ml DEAD in 5 mlanhydrous THF was added dropwise over 20 min. The reaction was warmed toRT and stirred for 45 min. A solution of 0.69 ml2-(2,4-Dichlorophenyl)-ethanol in 2 ml anhydrous THF was added withcooling. The reaction was stirred at RT for 3 h, then the solvents wereremoved under reduced pressure. The residue was treated withn-heptane:ethyl acetate/1:1. The filtrate was dried under reducedpressure. The product was purified by silica gel chromatography, elutingwith n-heptane:ethyl acetate/4:1 to n-heptane:ethyl acetate/1:1. Yield 2g.

4-Bromo-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid

2 g of 4-Bromo-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid methylester was dissolved in 10 ml of MeOH:water/3:1. 230 mg of lithiumhydroxide monohydrate were added to the solution, and the reaction wasstirred at RT for 16 h then at 50° C. for 2 h. The solution was cooledto RT, then acidified with half-concentrated hydrochloric acid. Thesuspension was concentrated under reduced pressure and then extractedwith ethyl acetate. The organic layer was dried over Na₂SO₄ and thesolvent was removed under reduced pressure to yield a white solid. Yield2.2 g

4-Bromo-3-[2-(2,4-dichloro-phenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

To a solution of 200 mg4-Bromo-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid in 4 ml CH₂Cl₂259 μl N-NEM and subsequently 168 mg TOTU were added. After stirring for1 h at RT 272 mgC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylamine tristrifluoroacetate in 1 ml CH₂Cl₂ were added and the mixture was stirredfor additional 2 h followed by removal of the solvent under reducedpressure. The residue was taken up in 3 ml saturated NaHCO₃ solution andfiltered through a chem elut® cartridge by elution with ethyl acetate.After concentration under reduced pressure and purification bypreparative HPLC (C18 reverse phase column, elution with a H₂O/MeCNgradient with 0.5% TFA) the fractions containing the product wereevaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 178 mg MS (ESI+): 563, chloro pattern

Analogously to example 77 the following compounds were prepared by asimilar procedure:

Example Structure MS (ESI+) 78

498, chloro pattern 79

499, chloro pattern 80

502, chloro pattern 81

518, chloro pattern 82

518, chloro pattern 83

514, chloro pattern 84

529, chloro pattern 85

485, chloro pattern 86

579, chloro pattern 87

485, chloro pattern

Example 883-[2-(2,4-Dichloro-phenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-4-trifluoromethyl-benzamide

3-Hydroxy-4-iodo-benzoic acid

To a solution of 26 g 3-Hydroxybenzoic acid and 43 g Na₂CO₃ in 45 mg H₂Oat 100° C. was added dropwise a solution of 48 g KI and 48 g iodine in135 ml H₂O. After heating for additional 3 h the mixture was cooled toRT and acidified with concentrated HCl. The title compound precipitatedas a white solid and was collected by filtration.

Yield 20 g

(ii) 3-Hydroxy-4-iodo-benzoic acid methyl ester

5 ml of thionyl chloride was added to 120 ml of MeOH at 0° C. Thesolution was stirred for 10 min and 20 g of 4-Iodo-3-hydroxy-benzoicacid was added. The reaction was stirred for 16 h at RT then heated to50° C. for 3 h. The solvents were removed under reduced pressure. Theresidue was used directly in the next step. Yield 21 g

(iii) 4-Iodo-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid methylester

6.6 g of triphenylphosphine and 5 g of 4-Iodo-3-hydroxy-benzoic acidmethyl ester were dissolved in 65 ml of anhydrous THF. The solution wascooled to 0 ° C. to 10° C. and a solution of 3.7 ml DEAD in 7.5 mlanhydrous THF was added dropwise over 20 min. The reaction was warmed toRT and stirred for 45 min. A solution of 2.8 ml2-(2,4-Dichlorophenyl)-ethanol in 3 ml anhydrous THF was added withcooling. The reaction was stirred at RT for 3 h, then the solvents wereremoved under reduced pressure. The residue was treated withn-heptane:ethyl acetate 1:1. The filtrate was dried under reducedpressure. The product was purified by silica gel chromatography, elutingwith n-heptane:ethyl acetate/4:1 to n-heptane:ethyl acetate/1:1.

Yield 8 g.

(iv) 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-trifluoromethyl-benzoic acidmethyl ester

To suspension of 800 mg4-Iodo-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid methyl ester, 520mg Cul and 160 mg KF in 5 ml DMF 0.57 ml chloro-difluoro-acetic acidmethyl ester were added dropwise at 120° C. and then stirred over night.After addition of 5 ml saturated aqueous NH₄Cl the suspension wasfiltered through a chem elut® cartridge by elution with ethyl acetate.After concentration under reduced pressure and purification bypreparative HPLC (C₁₈ reverse phase column, elution with a H₂O/MeCNgradient with 0.5% TFA) the fractions containing the product wereevaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 720 mg MS (ESI+): 451, chloro pattern

3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-trifluoromethyl-benzoic acid

500 mg of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-trifluoromethyl-benzoicacid methyl ester was dissolved in 10 ml of MeOH:water/3:1. 230 mg oflithium hydroxide monohydrate were added to the solution, and thereaction was stirred at RT for 16 h then at 50° C. for 2 h. The solutionwas cooled to RT, then acidified with half-concentrated hydrochloricacid. The solution was concentrated under reduced pressure and thenextracted with ethyl acetate. The organic layer was dried over Na₂SO₄and the solvent was removed under reduced pressure to yield a whitesolid.

Yield: 480 mg

3-[2-(2,4-Dichloro-phenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-4-trifluoromethyl-benzamide

To a solution of 200 mg3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-trifluoromethyl-benzoic acid in 4ml CH₂Cl₂ 1 ml N-NEM were added followed by 237 mg TOTU. After stirringfor 1 h at RT 282 mgC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylamine tristrifluoroacetate in 1 ml CH₂Cl₂ was added and the mixture was stirredfor additional 2 h followed by removal of the solvent under reducedpressure. The residue was taken up in 3 ml saturated NaHCO₃ solution andfiltered through a chem elut® cartridge by elution with ethyl acetate.After concentration under reduced pressure and purification bypreparative HPLC (C18 reverse phase column, elution with a H₂O/MeCNgradient with 0.5% TFA) the fractions containing the product wereevaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 180 mg MS (ESI+): 552, chloro pattern

Example 894-Cyano-3-[2-(2,4-dichloro-phenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

4-Cyano-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid methyl ester

A suspension of 800 mg 4-Iodo-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoicacid methyl ester, 180 mg C/CN, 312 mg Et₄NCN in 8 ml dioxane werepurged with argon for 10 min. Then 91 mg Pd₂(dba)₃ and 111 mg dppf wereadded and the mixture refluxed overnight. After addition of 5 mlsaturated aqueous NH₄Cl the suspension was filtered through a chem elut®cartridge by elution with ethyl acetate. After concentration underreduced pressure and purification by preparative HPLC (C₁₈ reverse phasecolumn, elution with a H₂O/MeCN gradient with 0.5% TFA) the fractionscontaining the product were evaporated and lyophilised.

Yield: 500 mg MS (ESI+): 350, chloro pattern

(ii) 4-Cyano-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid

500 mg of 4-Cyano-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid methylester was dissolved in 50 ml of MeOH:water/3:1. 1 g of lithium hydroxidemonohydrate was added to the added to the solution, and the reaction wasstirred at RT for 16 h and 2 h at 50° C. The solution was cooled to RT,then acidified with half-concentrated hydrochloric acid. The suspensionwas concentrated under reduced pressure and then extracted with ethylacetate. The organic layer was dried over Na₂SO₄ and the solvent wasremoved under reduced pressure to yield a white solid.

Yield: 480 mg

(iii)4-Cyano-3-[2-(2,4-dichloro-phenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

To a solution of 200 mg4-Cyano-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid in 4 ml CH₂Cl₂ 1ml N-NEM were added followed by 237 mg TOTU. After stirring for 1 h atRT 282 mg C-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetris trifluoroacetate in 1 ml CH₂Cl₂ were added and the mixture wasstirred for additional 2 h followed by removal of the solvent underreduced pressure. The residue was taken up in 3 ml saturated NaHCO₃solution and filtered through a chem elut® cartridge by elution withethyl acetate. After concentration under reduced pressure andpurification by preparative HPLC (C18 reverse phase column, elution witha H₂O/MeCN gradient with 0.5% TFA) the fractions containing the productwere evaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 124 mg MS (ESI+): 509, chloro pattern

Example 903-[3-(2,4-dichloro-phenyl)-ureido]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

3-[3-(2,4-dichloro-phenyl)-ureido]-benzoic acid

To a solution of 200 mg 3-Isocyanato-benzoic acid methyl ester in 2 mlethyl acetate is added dropwise a solution of 162 mg 2,4-dichloroanilinein 1 ml ethyl acetate. After 5 h at RT the solvent was removed underreduced pressure and the residue dissolved in 5 ml MeOH/THF/H₂O 2:2:1.100 mg lithium hydroxide monohydrate was added and the mixture stirredover night at RT. After removal of the solvent the residue was acidifiedby addition of 5 ml half concentrated HCl. The precipitating acid wasfiltered off and dried.

(ii)3-[3-(2,4-Dichloro-phenyl)-ureido]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

To a solution of 100 mg 3-[3-(2,4-Dichloro-phenyl)-ureido]-benzoic acidin 5 ml ethyl acetate 0.5 ml NEt₃ and 102 mg BOP-Cl were added. After 10min 100 mg C-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetris trifluoroacetate in 1 ml CH₂Cl₂ were added and the mixture stirredfor 2 h at RT followed by removal of the solvent under reduced pressure.The residue was taken-up in 3 ml saturated NaHCO₃ solution and filteredthrough a chem elut® cartridge by elution with ethyl acetate. Afterconcentration under reduced pressure and purification by preparativeHPLC (C18 reverse phase column, elution with a H₂O/MeCN gradient with0.5% TFA) the fractions containing the product were evaporated andlyophilised. The product was obtained as its trifluoroacetate salt.

Yield: 73 mg MS (ESI+): 498, chloro pattern

Example 913-[3-(5-Chloro-pyridin-2-yl)-ureido]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

This compound was prepared analogously to example 90 employing5-Chloro-pyridin-2-ylamine as amine component. MS (ESI+): 465, chloropattern

Example 923-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methylsulfanyl-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methylsulfanyl-benzoic acid

To a solution of 300 mg3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-fluoro-benzoic acid methyl ester in0.5 ml DMSO 70 mg NaSMe were added and stirred over night. Afteraddition of 0.3 ml H₂O and 20 mg lithium hydroxide monohydrate thesolution was stirred for 5 h and then acidified with diluted HCl. Themixture was extracted with ethyl acetate, the organic layer dried overNa₂SO₄. Removal of the solvent yielded the acid as a yellow solid.

(ii)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methylsulfanyl-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

To a solution of 120 mg3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methylsulfanyl-benzoic acid in 5 mlethyl acetate 0.5 ml NEt₃ and 102 mg BOP-Cl were added. After 10 min 100mg C-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylamine tristrifluoroacetate in 1 ml CH₂Cl₂ were added and the mixture stirred for10 h at RT followed by removal of the solvent under reduced pressure.The residue was taken up in 3 ml saturated NaHCO₃ solution and filteredthrough a chem elut® cartridge by elution with ethyl acetate. Afterconcentration under reduced pressure and purification by preparativeHPLC (C₁₈ reverse phase column, elution with a H₂O/MeCN gradient with0.5% TFA) the fractions containing the product were evaporated andlyophilised. The product was obtained as its trifluoroacetate salt.

Yield: 57 mg MS (ESI+): 530, chloro pattern

Example 933-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethoxy]-4-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethoxy]-4-methoxy-benzoicacid

To a solution of 145 mg 3-Hydroxy-4-methoxy-benzoic acid methyl ester in2 ml DMF 200 mg 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole[prepared as described in example 30] and 325 mg Cs₂CO₃ were added. Themixture was stirred for 3 h at RT and then diluted with 1 ml H₂O and 1ml EtOH. After addition of 500 mg lithium hydroxide monohydrate thesuspension was stirred over night. Subsequent removal of the solventunder reduced pressure and addition of diluted HCl yielded the acid as awhite precipitate that was collected by filtration.

(ii)3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethoxy]-4-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

To a solution of 180 mg3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethoxy]-4-methoxy-benzoicacid in 5 ml ethyl acetate 0.5 ml NEt₃ and 250 mg BOP-Cl were added.After 30 min 200 mgC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylamine tristrifluoro-acetate in 1 ml CH₂Cl₂ were added and the mixture stirred for10 h at RT followed by removal of the solvent under reduced pressure.The residue was taken up in 3 ml saturated NaHCO₃ solution and filteredthrough a chem elut® cartridge by elution with ethyl acetate. Afterconcentration under reduced pressure and purification by preparativeHPLC (C18 reverse phase column, elution with a H₂O/MeCN gradient with0.5% TFA) the fractions containing the product were evaporated andlyophilised. The product was obtained as its trifluoroacetate salt.

Yield: 157 mg MS (ESI+): 539, chloro pattern

Analogously to example 93 the following compounds were prepared by asimilar procedure:

Example Structure MS (ESI+) 94

509, chloro pattern 95

558 96

543, chloro pattern

Example 973-(6-Chloro-benzo[b]thiophene-2-sulfonylamino)-4-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

3-(6-Chloro-benzo[b]thiophene-2-sulfonylamino)-4-methoxy-benzoic acid

To a solution of 36 mg 3-Amino-4-methoxy-benzoic acid methyl esterin 1ml acetonitrile and 0.1 ml NEt₃ 50 mg6-Chloro-benzo[b]thiophene-2-sulfonyl chloride [prepared by a proceduredescribed by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, YongMi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.;Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, JohnZ.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B., PCTInt. Appl. (1999), 300 pp.WO99/37304] were added at RT. The mixture wasstirred at RT for 5 h, then diluted with 2 ml MeOH/THF/H₂O 2:2:1. Afteraddition of 100 mg lithium hydroxide monohydrate the suspension wasstirred over night. Subsequent removal of the solvent and addition ofdiluted HCl yielded the acid as a white precipitate, which was filteredoff.

(ii)3-(6-Chloro-benzo[b]thiophene-2-sulfonylamino)-4-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

To a solution of 80 mg3-(6-Chloro-benzo[b]thiophene-2-sulfonylamino)-4-methoxy-benzoic acid in5 ml ethyl acetate 0.1 ml NEt₃ and 100 mg BOP-Cl were added. After 30min 200 mg C-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetris trifluoro-acetate in 1 ml CH₂Cl₂ were added and the mixture stirredfor 10 h at RT followed by removal of the solvent under reducedpressure. The residue was taken up in 3 ml saturated NaHCO₃ solution andfiltered through a chem elut® cartridge by elution with ethyl acetate.After concentration under reduced pressure and purification bypreparative HPLC (C18 reverse phase column, elution with a H₂O/MeCNgradient with 0.5% TFA) the fractions containing the product wereevaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 44 mg MS (ESI+): 571, chloro pattern

Example 983-(2,4-Dichloro-benzylsulfamoyl)-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

3-(2,4-Dichloro-benzylsulfamoyl)-benzoic acid

To a solution of 1.3 g 2,4-Dichloro-benzylamine and 5 mg DMAP in 10 mlpyridine 1 g 3-Chlorosulfonyl-benzoic acid in 10 ml ethyl acetate wasadded dropwise. After stirring over night the solvent was removed underreduced pressure and the residue was taken up in 10 ml diluted HCl andextracted with ethyl acetate. The organic layer is dried over Na₂SO₄ andconcentrated to yield the acid as a yellow solid.

(ii)3-(2,4-Dichloro-benzylsulfamoyl)-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

To a solution of 100 mg 3-(2,4-Dichloro-benzylsulfamoyl)-benzoic acid in4 ml CH₂Cl₂ 259 μl N-NEM and subsequently 47 mg TOTU were added. Afterstirring for 1 h at RT 172 mgC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylamine tristrifluoro-acetate in 1 ml CH₂Cl₂ were added and the mixture was stirredfor additional 2 h followed by removal of the solvent under reducedpressure. The residue was taken up in 3 ml saturated NaHCO₃ solution andfiltered through a chem elut® cartridge by elution with ethyl acetate.After concentration under reduced pressure and purification bypreparative HPLC (C18 reverse phase column, elution with a H₂O/MeCNgradient with 0.5% TFA) the fractions containing the product wereevaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 32 mg MS (ESI+): 533, chloro pattern

Example 993-(5-Chloro-pyridin-2-ylsulfamoyl)-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

This compound was prepared analogously to example 95 employing5-Chloro-pyridin-2-ylamineas amine component. MS (ESI+): 486, chloropattern

Example 1003-[2-(2,4-Dichloro-phenyl)-acetylamino]-4-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

3-[2-(2,4-Dichloro-phenyl)-acetylamino]-4-methoxy-benzoic acid methylester

To a solution of 1.1 g 3-Amino-4-methoxy-benzoic acid methyl ester and 1g (2,4-Dichloro-phenyl)-acetic acid in 15 ml CH₂Cl₂, 2.7 ml NEt₃ and1.24 g BOP-Cl and 10 mg DMAP were added. After stirring over night thesolvent was removed under reduced pressure and the residue directlypurified by chromatography on silica with ethyl acetate/heptane 1:5→1:1to yield the ester as a yellow oil.

(ii) 3-[2-(2,4-Dichloro-phenyl)-acetylamino]-4-methoxy-benzoic acid

To a solution of 400 mg3-[2-(2,4-Dichloro-phenyl)-acetylamino]-4-methoxy-benzoic acid methylester in 5 ml MeOH/H₂O 2:1 56 mg lithium hydroxide monohydrate wereadded and the mixture was stirred over night. The suspension was dilutedwith 5 ml concentrated HCl to precipitate the acid. After filtration thefilter cake was washed twice with water and then dried to yield the acidas a white powder.

(iii)3-[2-(2,4-Dichloro-phenyl)-acetylamino]-4-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

To a solution of 150 mg3-[2-(2,4-Dichloro-phenyl)-acetylamino]-4-methoxy-benzoic acid in 4 mlCH₂Cl₂ 259 μl N-NEM and subsequently 70 mg TOTU were added. Afterstirring for 1 h at RT 268 mgC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylamine tristrifluoroacetate in 1 ml CH₂Cl₂ were added and the mixture was stirredfor additional 2 h followed by removal of the solvent under reducedpressure. The residue was taken up in 3 ml saturated NaHCO₃ solution andfiltered through a chem elut® cartridge by elution with ethyl acetate.After concentration under reduced pressure and purification bypreparative HPLC (C18 reverse phase column, elution with a H₂O/MeCNgradient with 0.5% TFA) the fractions containing the product wereevaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 97 mg MS (ESI+): 527, chloro pattern

Example 1015-[2-(2,4-Dichloro-phenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-isophthalamide

5-[2-(2,4-Dichloro-phenyl)-ethoxy]-isophthalic acid dimethyl ester

1.75 g of triphenylphosphine and 1 g of 5-Hydroxy-isophthalic aciddimethyl ester were dissolved in 17 ml of anhydrous THF. The solutionwas cooled to 0-10° C. and a solution of 1 ml DEAD in 1 ml anhydrous THFwas added dropwise over 20 min. The reaction was warmed to RT andstirred for 45 min. A solution of 11.3 ml 2-(2,4-Dichlorophenyl)-ethanolin 1 ml anhydrous THF was added with cooling. The reaction was stirredat RT for 16 h, then the solvents were removed under reduced pressure.The residue was treated with n-hepane:ethyl acetate/1:1. The filtratewas dried under reduced pressure and the product was purified by silicagel chromatography, eluting with n-heptane:ethyl acetate/4:1 ton-heptane:ethyl acetate/3:1.

(ii) 5-[2-(2,4-Dichloro-phenyl)-ethoxy]-isophthalic acid

500 mg 5-[2-(2,4-Dichloro-phenyl)-ethoxy]-isophthalic acid dimethylester were dissolved in 50 ml of MeOH:water/3:1. Then 1 g of lithiumhydroxide monohydrate was added the solution, and the reaction wasstirred at RT for 16 h and 2 h at 50° C. The solution was cooled to RTand then acidified with half-concentrated hydrochloric acid. Thesuspension was concentrated under reduced pressure and then extractedwith ethylacetate. The organic layer was dried over Na₂SO₄ and thesolvent was removed under reduced pressure to yield a white solid.

(iii) 5-[2-(2,4-Dichloro-phenyl)-ethoxy]-isophthalamic acid

To a solution of 100 mg 5-[2-(2,4-Dichloro-phenyl)-ethoxy]-isophthalicacid in 3 ml THF 46 mg N,N-carbonyldiimidazole was added at RT. After 1h 0.5 ml concentrated aqueous NH₃ solution were added and the reactionmixture was stirred for further 4 h. Concentration under reducedpressure and purification by preparative HPLC (C18 reverse phase column,elution with a H₂O/MeCN gradient with 0.5% TFA) the fractions containingthe product were evaporated and lyophilised to yield a white solid. Theproduct was obtained as its trifluoroacetate salt.

(iv)5-[2-(2,4-Dichloro-phenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-isophthalamide

To a solution of 40 mg 5-[2-(2,4-Dichloro-phenyl)-ethoxy]-isophthalamicacid in 2 ml CH₂Cl₂ 59 μl N-NEM and subsequently 37 mg TOTU were added.After stirring for 1 h at RT 43 mgC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylamine tristrifluoro-acetate in 1 ml CH₂Cl₂ were added and the mixture was stirredfor additional 2 h followed by removal of the solvent under reducedpressure. The residue was taken up in 3 ml saturated NaHCO₃ solution andfiltered through a chem elut® cartridge by elution with ethyl acetate.After concentration under reduced pressure and purification bypreparative HPLC (C18 reverse phase column, elution with a H₂O/MeCNgradient with 0.5% TFA) the fractions containing the product wereevaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 12 mg MS (ESI+): 527, chloro pattern

Example 1025-[2-(2,4-Dichloro-phenyl)-ethoxy]-1-oxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-nicotinamide

5-hydroxy-1-oxy-nicotinic acid methyl ester

To a solution of 600 mg 5-Hydroxy-nicotinic acid methyl ester in 8 mlCH₂Cl₂ 880 mg MCPBA were added at 0° C. After stirring at RT over nightthe solvent was removed under reduced pressure. The residue wasextracted with ethylacetate/heptane 1:1. The product was isolated afterfiltration as a white solid and used without further purification in thesubsequent reaction.

Yield: 600 mg.

(ii) 5-[2-(2,4-Dichloro-phenyl)-ethoxy]-1-oxy-nicotinic acid methylester

1.4 g of diphenyl-2-pyridylphosphine and 600 mg5-Hydroxy-1-oxy-nicotinic acid methyl ester and 0.5 ml2-(2,4-dichlorophenyl)-ethanol were dissolved in 16 ml of anhydrous THF.The solution was cooled to 0-10° C. and a solution of 1.22 g di-tert-butyl azodicarboxylate in 1 ml anhydrous THF was added dropwiseover 20 min. The reaction was warmed to RT and stirred over night. Afteraddition of 14 ml saturated methanolic HCl the reaction mixture wasstirred for 1 h and then the solvent was removed under reduced pressure.The residue was dissolved in CH₂Cl₂ and extracted with half-concentratedhydrochloric acid. The organic layer was evaporated and residuesubjected to the subsequent reaction without further purification.

Yield: 1.2 g

(iii) 5-[2-(2,4-Dichloro-phenyl)-ethoxy]-1-oxy-nicotinic acid

1.2 g 5-[2-(2,4-Dichloro-phenyl)-ethoxy]-1-oxy-nicotinic acid methylester were dissolved in 15 ml of MeOH/water 3:1. Then 200 mg of lithiumhydroxide monohydrate was added the solution, and the reaction wasstirred at RT for 16 h. The solution was acidified withhalf-concentrated hydrochloric acid under precipitation of the product.After filtration a white solid was obtained.

Yield: 900 mg

(iv)5-[2-(2,4-Dichloro-phenyl)-ethoxy]-1-oxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-nicotinamide

To a solution of 100 mg5-[2-(2,4-Dichloro-phenyl)-ethoxy]-1-oxy-nicotinic acid in 4 ml CH₂Cl₂150 μl N-NEM and subsequently 50 mg TOTU were added. After stirring for1 h at RT 223 mgC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylamine tristrifluoro-acetate in 1 ml CH₂Cl₂ were added and the mixture was stirredover night followed by removal of the solvent under reduced pressure.The residue was taken up in 3 ml saturated NaHCO₃ solution and filteredthrough a chem elut® cartridge by elution with ethyl acetate. Afterconcentration under reduced pressure and purification by preparativeHPLC (C18 reverse phase column, elution with a H₂O/MeCN gradient with0.5% TFA) the fractions containing the product were evaporated andlyophilised. The product was obtained as its trifluoroacetate salt.

Yield: 55 mg MS (ESI+): 501, chloro pattern

Example 1033-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(4-pyridin-4-yl-phenyl)-benzamide

3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methoxy-benzamidoyl-4-phenyl-boronicacid

To a solution of 3.8 g3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid in 20 mlCH₂Cl₂ 5.6 ml N-NEM and subsequently 3.6 g TOTU were added. Afterstirring for 1 h at RT 4-aminophenyl boronic acid 10 ml CH₂Cl₂ wereadded and the mixture was over night followed by removal of the solventunder reduced pressure. The residue was taken up in 10 ml saturatedNaHCO₃ solution and filtered through a chem elut® cartridge by elutionwith ethyl acetate. After concentration under reduced pressure theresidue was subjected to the subsequent reaction without furtherpurification.

(ii)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(4-pyridin-4-yl-phenyl)-benzamide

A mixture of 100 mg3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methoxy-benzamidoyl-4-phenyl-boronicacid, 64 mg 4-Brompyridine hydrochloride, 0.2 ml aqueous Na₂CO₃ (10M) in5 ml dme were purged with argon for 10 min. Then 5 mg Pd(PPh₃)₃ wereadded under argon and the mixture refluxed overnight. The residue wastaken up in 3 ml saturated NaHCO₃ solution and filtered through a chemelut® cartridge by elution with ethyl acetate. Subsequent removal of thesolvent under reduced pressure and purification by preparative HPLC (C₁₈reverse phase column, elution with a H₂O/MeCN gradient with 0.5% TFA)the fractions containing the product were evaporated and lyophilised.The product was obtained as its trifluoroacetate salt.

Yield: 8 mg MS (ESI−): 493, chloro pattern

Analogously to example 103 the following compounds were prepared by asimilar procedure:

Example Structure MS (ESI+) 104

523, chloro pattern 105

535, chloro pattern 106

494, chloro pattern 107

493, chloro pattern 108

494, chloro pattern 109

517, chloro pattern 110

626, chloro pattern 111

508 chloro pattern 112

517, chloro pattern 113

510, chloro pattern 114

528, chloro pattern 115

523, chloro pattern 116

493, chloro pattern

Example 1172-[2-(2,4-Dichloro-phenyl)-ethoxy]-N4-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-terephthalamide

3-[2-(2,4-Dichloro-phenyl)-ethoxy]-terephthalamic acid methyl ester

To a solution of 100 mg4-Cyano-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid methyl ester in2 ml DMSO 93 mg K₂CO₃ and 68 μl H₂O₂ (35%) were added at RT. Afterstirring the reaction over night the mixture was taken up in 5 ml ethylacetate and 3 ml water and filtered through a chem elut® cartridge byelution with ethyl acetate. After removal of the solvent the crudeproduct was subjected to the subsequent reaction.

Yield: 103 mg

(ii) 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-terephthalamic acid

103 mg of 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-terephthalamic acid methylester were dissolved in 1.2 ml of MeOH/water 3:1. 14 mg of lithiumhydroxide monohydrate were added to the added to the solution, and thereaction was stirred at RT for 16 h and 2 h at 50° C. The solution wascooled to RT, then acidified with half-concentrated hydrochloric acid.The suspension was concentrated under reduced pressure and thenextracted with ethyl acetate. The organic layer was dried over Na₂SO₄and the solvent was removed under reduced pressure to yield a whitesolid.

Yield: 50 mg

(iii)2-[2-(2,4-Dichloro-phenyl)-ethoxy]-N4-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-terephthalamide

To a solution of 50 mg 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-terephthalamicacid in 2 ml CH₂Cl₂ 100 μl N-NEM and subsequently 27 mg TOTU were added.After stirring for 1 h at RT 82 mgC-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylamine tristrifluoro-acetate in 1 ml CH₂Cl₂ were added and the mixture was stirredfor additional 2 h followed by removal of the solvent under reducedpressure. The residue was taken up in 3 ml saturated NaHCO₃ solution andfiltered through a chem elut® cartridge by elution with ethyl acetate.After concentration under reduced pressure and purification bypreparative HPLC (C18 reverse phase column, elution with a H₂O/MeCNgradient with 0.5% TFA) the fractions containing the product wereevaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 8 mg MS (ESI+): 527, chloro pattern

Example 1184-Acetylamino-3-[2-(2,4-dichloro-phenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

To a solution of 50 mg4-Amino-3-[2-(2,4-dichloro-phenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamideand 42 μl NEt₃ in 1 ml acetonitrile 30 μl acetic acid anhydride wereadded at RT. After stirring the reaction over night the mixture wastaken up in 3 ml saturated NaHCO₃ solution and filtered through a chemelut® cartridge by elution with ethyl acetate. After concentration underreduced pressure and purification by preparative HPLC (C18 reverse phasecolumn, elution with a H₂O/MeCN gradient with 0.5% TFA) the fractionscontaining the product were evaporated and lyophilised. The product wasobtained as its trifluoroacetate salt.

Yield: 15 mg MS (ESI+): 541, chloro pattern

Example 1193-[2-(2,4-Dichloro-phenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-4-ureido-benzamide

A solution of 50 mg4-Amino-3-[2-(2,4-dichloro-phenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamideand 13 mg KCNO in 2 ml acetic was stirred reaction over night at RT. Themixture was taken up in 5 ml saturated NaHCO₃ solution and filteredthrough a chem elut® cartridge by elution with ethyl acetate. Afterconcentration under reduced pressure and purification by preparativeHPLC (C18 reverse phase column, elution with a H₂O/MeCN gradient with0.5% TFA) the fractions containing the product were evaporated andlyophilised. The product was obtained as its trifluoroacetate salt.

Yield: 8 mg MS (ESI+): 541, chloro pattern

Example 1203-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methylamino-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methylamino-benzoic acid methylester

To a solution of 500 mg4-Amino-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid methyl ester in2.5 ml acetonitrile 0.5 ml Mel were added and stirred over night at RT.After concentration under reduced pressure and purification bypreparative HPLC (C18 reverse phase column, elution with a H₂O/MeCNgradient with 0.5% TFA) the fractions containing the product wereevaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

(ii) 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methylamino-benzoic acid

To a solution of 100 mg3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methylamino-benzoic acid methylester in 3 ml of MeOH:water/3:1, 14 mg of lithium hydroxide monohydratewere added and the reaction was stirred at RT for 16 h. The solution wasacidified with half-concentrated hydrochloric acid and the solvent wasevaporated. The crude acid was subjected to the subsequent amidecoupling without further purification.

(iii)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methylamino-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

To a solution of 60 mg3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methylamino-benzoic acid in 1 mlCH₂Cl₂ 100 μl N-NEM and subsequently 30 mg TOTU were added. Afterstirring for 1 h at RT 106 mgC-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylamine tristrifluoro-acetate in 1 ml CH₂Cl₂ were added and the mixture was stirredover night followed by removal of the solvent under reduced pressure.The residue was taken up in 3 ml saturated NaHCO₃ solution and filteredthrough a chem elut® cartridge by elution with ethyl acetate. Afterconcentration under reduced pressure and purification by preparativeHPLC (C18 reverse phase column, elution with a H₂O/MeCN gradient with0.5% TFA) the fractions containing the product were evaporated andlyophilised. The product was obtained as its trifluoroacetate salt.

Yield: 12 mg MS (ESI+): 513, chloro pattern

Example 1213-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-formylamino-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

A solution of 50 mg4-Amino-3-[2-(2,4-dichloro-phenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamidein 0.2 ml formic acid were heated to 100° C. for 1 h. The mixture waspurified by preparative HPLC (C18 reverse phase column, elution with aH₂O/MeCN gradient with 0.5% TFA) and the fractions containing theproduct were evaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 25 mg MS (ESI+): 527, chloro pattern

Example 122{2-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-[(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-carbamoyl]-phenyl}-carbamicacid methyl ester

To a solution of 50 mg4-Amino-3-[2-(2,4-dichloro-phenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide,20 μl NEt₃ in 1 ml CH₂Cl₂ 10 μl chloroformic acid methyl ester wereadded at RT. After stirring over night the mixture was concentrated andpurified by preparative HPLC (C18 reverse phase column, elution with aH₂O/MeCN gradient with 0.5% TFA) and the fractions containing theproduct were evaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 25 mg MS (ESI+): 557, chloro pattern

Example 123N-[1-(4-Chloro-phenyl)-piperidin-4-yl]-3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methoxy-benzamide

4-{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-piperidine-1-carboxylicacid tert-butyl ester

To a solution of 1 g3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid in 15 mlCH₂Cl₂ 1.5 ml N-NEM and subsequently 962 mg TOTU were added. Afterstirring for 1 h at RT 881 mg Boc-(4-amino)piperidine in 5 ml CH₂Cl₂were added and the mixture was stirred for additional 2 h followed byaddition of 20 ml saturated NaHCO₃ solution. The organic layer wasseparated and dried over Na₂SO₄ and the solvent evaporated. The residuewas recrystallized from ethyl acetate/heptane to afford a white powder.

Yield: 1.4 g

(ii)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-yl-benzamide

1.4 g4-{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-piperidine-1-carboxylicacid tert-butyl ester was suspended in 20 ml HCl in ethanol at RT. After2 h a clear solution was obtained. Addition of 50 ml toluene followed byevaporation of the solvent and repeatedly coevaporation of the residuewith toluene yielded the product as a white foam.

Yield: 1 g

(iii)N-[1-(4-Chloro-phenyl)-piperidin-4-yl]-3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methoxy-benzamide

A mixture of 100 mg3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-yl-benzamidehydrochloride (0.2 mmol), 62 mg (0.33 mmol) 4-Bromochlorobenzene, 73 mgsodium-t-butoxide in 5 ml dioxane were purged with argon for 10 min.Then 37 mg of 2-(Dicyclohexylphosphino)biphenyl and 20 mg Pd₂(dba)₃ wereadded under argon and the mixture refluxed overnight. The residue wastaken up in 3 ml saturated NaHCO₃ solution and filtered through a chemelut® cartridge by elution with ethyl acetate. Subsequent removal of thesolvent under reduced pressure and purification by preparative HPLC (C18reverse phase column, elution with a H₂O/MeCN gradient with 0.5% TFA)the fractions containing the product were evaporated and lyophilised.The product was obtained as its trifluroacetate salt.

Yield: 3 mg MS (ESI+): 533, chloro pattern

Analogously to example 123 the following compounds were prepared by asimilar procedure:

Example Structure MS (ESI+) 124

530, chloro pattern 125

516, chloro pattern 126

501, chloro pattern 127

524, chloro pattern

Example 128N-(1-Cyclohexyl-piperidin-4-yl)-3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methoxy-benzamide

To a solution of 100 mg3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-yl-benzamidehydrochloride and 43 mg cyclohexanone in 2 ml acetonitrile 27 mgNa(CN)BH₃ were introduced. After stirring at RT overnight the reactionmixture was heated to 80° C. for 4 h. After removal of the solvent underreduced pressure and purification by preparative HPLC (C₁₈ reverse phasecolumn, elution with a H₂O/MeCN gradient with 0.5% TFA) the fractionscontaining the product were evaporated and lyophilised. The product wasobtained as its trifluoroacetate salt.

Yield: 26 mg MS (ESI+): 505, chloro pattern

Analogously to example 128 the following compounds were prepared by asimilar procedure:

Example Structure MS (ESI+) 129

507, chloro pattern 130

506, chloro pattern 131

563, chloro pattern

Example 1323-[2-(5-Chloro-pyridin-2-yl)-ethoxy]-4-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

5-Chloro-2-vinyl-pyridine

A solution of 2 g 2,5-dichloropyridine and 4.3 g tributylvinylstannanein 20 ml toluene was purged with argon for 15 min. Then 50 mg Pd(PPh₃)₄was added under argon and the reaction mixture was refluxed for 3 h.After removal of the solvent under reduced pressure the residue wastaken up in ethyl acetate and saturated aqueous KF solution. Filtrationthrough a chem elut® cartridge by elution with ethyl acetate andevaporation of the solvent yielded a slightly brown oil.

Yield: 2 g

(ii) 2-(5-Chloro-pyridin-2-yl)-ethanol

To a solution of 2 g 5-Chloro-2-vinyl-pyridine in 10 ml THF was addeddropwise 86 ml of a 9-BBN solution in THF (0.5 M) at RT. After 1 h 2.2ml of a aqueous NaOH solution (10%) were added cautiously followed bythe addition of 25 ml H₂O₂ (35%). This reaction mixture was stirred overnight at RT. Then saturated Na₂SO₃ solution and 20 ml ethylacetate wasadded and the organic layer was separated. After removal of the solventunder reduced pressure and purification by preparative HPLC (C₁₈ reversephase column, elution with a H₂O/MeCN gradient with 0.5% TFA) thefractions containing the product were evaporated and lyophilised. Theproduct was obtained as its trifluoroacetate salt.

Yield: 1.5 g

(iii) 3-[2-(5-Chloro-pyridin-2-yl)-ethoxy]-4-methoxy-benzoic acid methylester

To a solution of 400 mg 3-Hydroxy-4-methoxy-benzoic acid methyl ester,346 mg 2-(5-Chloro-pyridin-2-yl)-ethanol, 1800 mg polymerbound triphenylphosphine (Fluka, 3 mmol triphenylphosphine/g resin) and 1015 μl DEADwere introduced and the mixture was shaken over night at RT. Afterfiltration, evaporation of the solvent the residue was purified bypreparative HPLC (C₁₈ reverse phase column, elution with a H₂O/MeCNgradient with 0.5% TFA) and the fractions containing the product wereevaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 530 mg

(iv) 3-[2-(5-Chloro-pyridin-2-yl)-ethoxy]-4-methoxy-benzoic acid

85 mg 3-[2-(5-Chloro-pyridin-2-yl)-ethoxy]-4-methoxy-benzoic acid methylester was dissolved in 1.2 ml of MeOH:water/3:1. 30 mg of lithiumhydroxide monohydrate were added to the added to the solution, and thereaction was stirred at RT for 16 h. The reaction mixture was acidifiedwith half-concentrated hydrochloric acid. The suspension wasconcentrated under reduced pressure, coevaporated twice with toluene(2×10 ml) and then directly subjected to the subsequent amide coupling.

Yield. 50 mg

3-[2-(5-Chloro-pyridin-2-yl)-ethoxy]-4-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

To a solution of 50 mg3-[2-(5-Chloro-pyridin-2-yl)-ethoxy]-4-methoxy-benzoic acid in 5 mlethyl acetate 0.1 ml NEt₃ and 100 mg BOP-Cl were added. After 30 min 200mg C-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylamine tristrifluoro-acetate in 1 ml CH₂Cl₂ were added and the mixture stirred for10 h at RT followed by removal of the solvent under reduced pressure.The residue was taken up in 3 ml saturated NaHCO₃ solution and filteredthrough a chem elut® cartridge by elution with ethyl acetate. Afterconcentration under reduced pressure and purification by preparativeHPLC (C18 reverse phase column, elution with a H₂O/MeCN gradient with0.5% TFA) the fractions containing the product were evaporated andlyophilised. The product was obtained as its trifluoroacetate salt.

Yield: 16 mg MS (ESI+): 480, chloro pattern

Example 1334-Chloro-3-[2-(5-Chloro-pyridin-2-yl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

This compound was prepared analogously to example 132 employing4-Chloro-3-hydroxy-benzoic acid ethyl ester coupling component. MS(ESI+): 485, chloro pattern

Example 1343-[2-(5-Chloro-pyridin-2-yl)-ethoxy]-4-Fluoro-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

This compound was prepared analogously to example 132 employing4-Fluoro-3-hydroxy-benzoic acid ethyl ester coupling component. MS(ESI+): 569, chloro pattern

Example 135N-[1-(3-Acetylamino-phenyl)-piperidin-4-ylmethyl]-3-[2-(2,4-dichloro-phenyl)-ethoxy]-4methoxy-benzamide

To a solution of 50 mg3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamidehydrochloride, 38 mg 3-acetamidoboronic acid in 1 ml CH₂Cl₂ 100 mgmolsieve 3 Å, 38.5 mg Cu(OAc)₂ and 25 μl pyridine were added. Thesuspension was stirred for 3 d, then 3 ml saturated NaHCO₃ solution wereadded and the mixture filtered through a chem elut® cartridge by elutionwith ethyl acetate. After concentration under reduced pressure andpurification by preparative HPLC (C18 reverse phase column, elution witha H₂O/MeCN gradient with 0.5% TFA) the fractions containing the productwere evaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 2 mg MS (ESI+):, chloro pattern

Analogously to example 135 the following compounds were prepared by asimilar procedure:

Example Structure MS (ESI+) 136

571, chloro pattern 137

543, chloro pattern 138

556, chloro pattern

Example 1393-[1-(4-Chloro-phenyl)-cyclobutylmethoxy]-4-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

[1-(4-Chloro-phenyl)-cyclobutyl]-methanol

To a solution of 1 g 1-(4-Chloro-phenyl)-cyclobutanecarboxylic acid in15 ml THF were added dropwise at 0° C. 9.5 ml BH₃*THF in THF (1M). Thenthe reaction mixture was heated at reflux for 2 h and then cooled againto 0° C. followed by cautious addition of 30 ml methanol. Afterevaporation of the solvents the residue was codestilled twice withtoluene. The crude product was subjected to the subsequent reactionwithout further purification.

(ii) 3-[1-(4-Chloro-phenyl)-cyclobutylmethoxy]-4-methoxy-benzoic acid

To a solution of 300 mg 3-Hydroxy-4-methoxy-benzoic acid methyl ester,388 mg [1-(4-Chloro-phenyl)-cyclobutyl]-methanol 1645 mg polymerboundtriphenyl phosphine (Fluka, 3 mmol triphenyl phosphine/g resin) and 762μl DEAD were introduced and the mixture was shaken over night at RT.After filtration, evaporation of the solvent the residue was taken up in5 ml MeOH/H₂O 3:1 and 20 mg LiOH monohydrate was added. After heatingthe mixture at 60° C. for 2 h the mixture was acidified with halfconcentrated HCl and filtered through a chem elut® cartridge by elutionwith ethyl acetate. After concentration under reduced pressure the crudeproduct was subjected to the following amide coupling without furtherpurification.

(iii)3-[1-(4-Chloro-phenyl)-cyclobutylmethoxy]-4-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

To a solution of 50 mg acid in 5 ml ethyl acetate 0.1 ml NEt₃ and 100 mgBOP-Cl were added. After 30 min 111 mgC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylamine tristrifluoro-acetate in 1 ml CH₂Cl₂ were added and the mixture stirred for10 h at RT followed by removal of the solvent under reduced pressure.The residue was taken up in 3 ml saturated NaHCO₃ solution and filteredthrough a chem elut® cartridge by elution with ethyl acetate. Afterconcentration under reduced pressure and purification by preparativeHPLC (C18 reverse phase column, elution with a H₂O/MeCN gradient with0.5% TFA) the fractions containing the product were evaporated andlyophilised. The product was obtained as its trifluoroacetate salt.

Yield: 10 mg MS (ESI+): 520, chloro pattern

Analogously to example 139 the following compounds were prepared by asimilar procedure:

Example Structure MS (ESI+) 140

506, chloro pattern 141

505, chloro pattern 142

502, chloro pattern 143

460, chloro pattern 144

480, chloro pattern 145

480, chloro pattern

Example 1463-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-[1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperidin-4-ylmethyl]-benzamide

[4-({3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-methyl)-piperidin-1-yl]-aceticacid

To 1 g3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-ylmethyl-benzamidehydrochloride and 400 mg NaOH in 50 ml EtOH/H₂O 1:1 0.35 g bromo aceticacid were added at RT. After stirring over night the reaction mixturewas acidified with half concentrated HCl. After evaporation of thesolvent the residue was coevaporated with toluene. The waxy brown solidwas subjected to the subsequent reaction without further purification.

Yield: 1.1 g

(ii)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-[1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperidin-4-ylmethyl]-benzamide

To a solution of 60 mg[4-({3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-methyl)-piperidin-1-yl]-aceticacid, 100 μl NEt₃ in 2 ml THF 30 mg CDI was added and the reactionmixture stirred for 2 h at RT. Then 18 mg pyrrolidine were added and thereaction was stirred for further 16 h . After removal of the solvent theresidue was directly purified by preparative HPLC (C18 reverse phasecolumn, elution with a H₂O/MeCN gradient with 0.5% TFA). The fractionscontaining the product were evaporated and lyophilised. The product wasobtained as its trifluoroacetate salt.

Yield: 12 mg MS (ESI+): 547, chloro pattern

Analogously to example 146 the following compounds were prepared by asimilar procedure:

Example Structure MS (ESI+) 147

564, chloro pattern 148

564, chloro pattern 149

576, chloro pattern 150

562, chloro pattern 151

576, chloro pattern 152

577, chloro pattern 153

560, chloro pattern 154

587, chloro pattern 155

522, chloro pattern 156

576, chloro pattern 157

536, chloro pattern

Example 1583-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-[1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperidin-4-yl]-benzamide

(4-{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-piperidin-1-yl)-aceticacid

To 360 mg3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-piperidin-4-yl-benzamidehydrochloride and 162 mg NaOH in 20 ml EtOH/H₂O 1:1 142 mg bromo aceticacid was added at RT. After stirring over night the reaction mixture wasacidified with half concentrated HCl. After evaporation of the solventthe residue was coevaporated with toluene. The waxy brown solid wassubjected to the subsequent reaction without further purification.

Yield: 330 mg

(iii)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-[1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperidin-4-yl]-benzamide

To a solution of 60 mg(4-{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-piperidin-1-yl)-aceticacid, 100 μl NEt₃ in 2 ml DMF 30 mg CDI was added and the reactionmixture stirred for 2 h at RT. Then 18 mg pyrrolidine were added and thereaction was stirred for further 16 h . After removal of the solvent theresidue was directly purified by preparative HPLC (C18 reverse phasecolumn, elution with a H₂O/MeCN gradient with 0.5% TFA). The fractionscontaining the product were evaporated and lyophilised. The product wasobtained as its trifluoroacetate salt.

Yield: 22 mg MS (ESI+): 534, chloro pattern

Analogously to example 158 the following compounds were prepared by asimilar procedure:

Example Structure MS (ESI+) 159

522, chloro pattern 160

563, chloro pattern 161

537, chloro pattern 162

550, chloro pattern

Example 1632-{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-3-furo[3,2-c]pyridin-2-yl-propionicacid methyl ester

3-Iodo-pyridin-4-ol

A solution of 20 g 4-hydroxypyridine and 13 g Na₂SO₄ in 50 ml water washeated to 100° C. To this mixture a solution of 27 g I₂, 28 g KI wasadded dropwise. After 3 h the mixture was washed with ethylacetate.Concentration of the aqueous layer led to precipitation of the product,which was isolated by filtration:

Yield: 12.5 g

(ii)2-{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-pent-4-ynoicacid methyl ester

To a solution of 1 g3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid in 15 mlCH₂Cl₂ 1.5 ml N-N EM and subsequently 1.1 g TOTU were added. Afterstirring for 1 h at RT 500 mg 2-Amino-pent-4-ynoic acid methyl esterhydrochloride in 5 ml CH₂Cl₂ were added and the mixture was stirred overnight followed by addition of 20 ml saturated NaHCO₃ solution. Theorganic layer was separated and dried over Na₂SO₄ and the solventevaporated. The residue was purified by preparative HPLC (C18 reversephase column, elution with a H₂O/MeCN gradient with 0.5% TFA) and thefractions containing the product were evaporated and lyophilised. Theproduct was obtained as its trifluoroacetate salt.

Yield: 1.4 g

(iii)2-{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-3-furo[3,2c]Pyridin-2-yl-propionicacid methyl ester

A solution of 100 mg2-{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-pent-4-ynoicacid methyl ester, 74 mg 3-Iodo-pyridin-4-ol, 123 μl NEt₃, 1 mg Cul in 3ml DMF was purged with argon for 15 min. Then 8 mg Pd(PPh₃)₂Cl₂, wereadded under argon and the mixture was heated to 100° C. for 2 h. Aftercooling to 50° C. 66 μl DBU was added, followed by stirring for 2 h atthis temperature. The residue was taken up in 3 ml saturated NaHCO₃solution and filtered through a chem elut® cartridge by elution withethyl acetate. Subsequent removal of the solvent under reduced pressureand purification by preparative HPLC (C18 reverse phase column, elutionwith a H₂O/MeCN gradient with 0.5% TFA) the fractions containing theproduct were evaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 6 mg

Example 1642-{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-3-(1H-pyrrolo[3,2-c]pyridin-2-yl)-propionicacid methyl ester

(3-Iodo-pyridin-4-yl)-carbamic acid tert-butyl ester

To a solution of 20 g 4-aminopyridine in 50 ml acetic acid 46 g lCl wereadded at RT. The reaction mixture was heated to 100° C. for 4 h and thenquenched with 100 ml water. The pH was adjusted to 9 by addition ofNa₂CO₃ solution followed by addition of Na₂SO₃. Extraction of theaqueous solution was done with ethylacetate. The organic layer was driedover Na₂SO₄ and the solvent removed under reduced pressure. The residuewas dissolved in 70 ml CH₂Cl₂ and 15 ml NEt₃. Then 20 g Boc₂O were addedat RT and the reaction mixture was stirred over night. After removal ofthe solvent the residue was chromatographied on silica gel withheptane/ethylacetate to yield a brown solid.

Yield: 20 g

(ii)2-(2-{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-2-methoxycarbonyl-ethyl)-pyrrolo[3,2-c]pyridine-1-carboxylicacid tert-butyl ester

A solution of 100 mg2-{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-pent-4-ynoicacid methyl ester, 106 mg (3-Iodo-pyridin-4-yl)-carbamic acid tert-butylester, 123 μl NEt₃, 1 mg Cul in 3 ml DMF was purged with argon for 15min. Then 8 mg Pd(PPh₃)₂Cl₂ were added under argon and the mixture washeated to 100° C. for 2 h. After cooling to 50° C. 66 μl DBU was added,followed by stirring for 2 h at this temperature. The residue was takenup in 3 ml saturated NaHCO₃ solution and filtered through a chem elut®cartridge by elution with ethyl acetate. Subsequent removal of thesolvent under reduced pressure and purification by preparative HPLC (C18reverse phase column, elution with a H₂O/MeCN gradient with 0.5% TFA)the fractions containing the product were evaporated and lyophilised.The product was obtained as its trifluoroacetate salt.

Yield: 9 mg

(iii) 2-{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-3-(1H-pyrrolo[3,2-c]pyridin-2-yl)-propionic acid methyl ester

To a solution of 9 mg2-(2-{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-2-methoxycarbonyl-ethyl)-pyrrolo[3,2-c]pyridine-1-carboxylicacid tert-butyl ester in 1 ml CH₂Cl₂ 0.5 ml TFA was added dropwise at 0°C. After 1 h 5 ml toluene were added and the solvent removed underreduced pressure to yield a brown foam. The product was obtained as itstrifluoroacetate salt. Yield: 5 mg

Example 1653-[2-(2,4-Dichloro-phenyl)-ethoxy]-N-(2′-Hydroxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-4-methoxy-benzamide

(2′-Hydroxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-carbamicacid tert-butyl ester

To a solution of 500 mg 2,4 dihydroxypyridine in DMF 216 mg NaH (60% inmineral oil) were added at RT. After 30 minN-phenyltrifluoromethanesulfonamide was added and the mixture stirredfor 1 h. Then 960 mg (boc-aminomethyl)piperidine were added and thereaction mixture stirred over night. After of water and extraction withethylacetate the organic layer was dried over Na₂SO₄. Subsequent removalof the solvent under reduced pressure and purification by preparativeHPLC (C18 reverse phase column, elution with a H₂O/MeCN gradient with0.5% TFA) the fractions containing the product were evaporated andlyophilised. The product was obtained as its trifluoroacetate salt.

Yield: 1.2 g

(ii) 4-Aminomethyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-ol

To a solution of 500 mg(2′-Hydroxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-carbamicacid tert-butyl ester in 5 ml CH₂Cl₂ 3 ml TFA was added dropwise at 0°C. After 16 h 20 ml toluene were added and the solvent removed underreduced pressure to yield a brown foam.

Yield: 503 mg

(iii)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-N-(2′-Hydroxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-4-methoxy-benzamide

To a solution of 200 mg3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid in 5 ml CH₂Cl₂300 μl N-NEM and subsequently 192 mg TOTU were added. After stirring for1 h at RT 243 mg4-Aminomethyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-ol tristrifluoro-acetate in 1 ml CH₂Cl₂ were added and the mixture was stirredfor over night followed by removal of the solvent under reducedpressure. The residue was taken up in 5 ml saturated NaHCO₃ solution andfiltered through a chem elut® cartridge by elution with ethyl acetate.After concentration under reduced pressure and purification bypreparative HPLC (C18 reverse phase column, elution with a H₂O/MeCNgradient with 0.5% TFA) the fractions containing the product wereevaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 85 mg MS (ESI+): 530, chloro pattern

Example 1663-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(1-pyrimidin-4-yl-piperidin-4-ylmethyl)-benzamide

[1-(2-Chloro-pyrimidin-4-yl)-piperidin-4-ylmethyl]-carbamic acidtert-butyl ester

Piperidin-4-ylmethyl-carbamic acid tert-butyl ester (2 g, 9.33 mmol),2,4-dichloro-pyrimidine (1.67 g, 11.2 mmol) and ethyl-diisopropyl-amine(2,41 g, 18.66 mmol) were heated under reflux in 100 ml of ethanol for 4hours. The reaction mixture was evaporated, dissolved in ethyl acetateand extracted with aqueous solution (pH4). The organic layer was driedwith MgSO₄ and evaporated to yield a mixture of the main isomer[1-(2-chloro-pyrimidin-4-yl)-piperidin-4-ylmethyl]-carbamic acidtert-butyl ester and traces of[1-(4-chloro-pyrimidin-2-yl)-piperidin-4-ylmethyl]-carbamic acidtert-butyl ester.

Yield: 2.67 g (87%) MS: 327.1/329.1 (M+H)⁺.(ii) (1-Pyrimidin-4-yl-piperidin-4-ylmethyl)-carbamic acid tert-butylester

[1-(2-chloro-pyrimidin-4-yl)-piperidin-4-ylmethyl]-carbamic acidtert-butyl (400 mg) was dissolved in 100 ml of methanol. After additionof 50 mg of palladium on charcoal (10%) hydrogen was introduced in ashaking apparatus for 3 hours. After filtration of the catalyst thesolution was evaporated.

Yield: 350 mg MS: 293.2 (M+H)⁺.(iii) C-(1-Pyrimidin-4-yl-piperidin-4-yl)-methylamine

(1-Pyrimidin-4-yl-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester(400 mg) and 50% aqueous trifluoro-acetic acid (5 ml) were stirred 24hours at room temperature. The mixture was evaporated and lyophilised.The product was obtained as its trifluoroacetate salt.

Yield: 519 mg, MS: 193.2 (M+H)⁺.

(iv)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-N-(1-pyrimidin-4-yl-piperidin-4-ylmethyl)-benzamide

To a solution of 70 mg3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid in 3 ml CH₂Cl₂200 μl N-NEM and subsequently 120 mg TOTU were added. After stirring for1 h at RT 120 mg C-(1-Pyrimidin-4-yl-piperidin-4-yl)-methylamine tristrifluoro-acetate in 1 ml CH₂Cl₂ were added and the mixture was stirredfor over night followed by removal of the solvent under reducedpressure. The residue was taken up in 5 ml saturated NaHCO₃ solution andfiltered through a chem elut® cartridge by elution with ethyl acetate.After concentration under reduced pressure and purification bypreparative HPLC (C18 reverse phase column, elution with a H₂O/MeCNgradient with 0.5% TFA) the fractions containing the product wereevaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 8 mg MS (ESI+): 530, chloro pattern

Example 1674-Chloro-3-[2-(6-chloro-pyridin-3-yl)-ethoxy]-N-(2′-methyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

(2′-Methyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-carbamicacid tert-butyl ester

A suspension of 1 g piperidin-4-ylmethyl-carbamic acid tBu ester 0.65 g4-chloropicoline in 5 ml n-BuOH/H₂O/NEt₃ 1:1:1 was refluxed for 3 days.After removal of the solvent under reduced pressure the residue waspurified by chromatography on silica with CH₂Cl₂/MeOH100:1→50:1→10:1-5:1 to yield a white solid.(ii)C-(2′-Methyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetris trifluoroacetate

To a solution of 1.24(2′-Methyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-carbamicacid tert-butyl ester in 5 ml CH₂Cl₂ 2 ml TFA were added at RT. Afterstirring for 30 min the solution was diluted with 20 ml of toluene andevaporated under reduced pressure. The residue was codestilled twicewith toluene and then used in the subsequent reactions without furtherpurification

(iii)4-Chloro-3-[2-(6chloro-pyridin-3-yl)-ethoxy]-N-(2′-methyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

To a solution of 100 mg3-[2-(5-Chloro-pyridin-2-yl)-ethoxy]-4-methoxy-benzoic acid in 5 mlethyl acetate 0.1 ml NEt₃ and 150 mg BOP-Cl were added. After 30 min 124mgC-(2′-Methyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetris trifluoroacetate tris trifluoro-acetate in 1 ml CH₂Cl₂ were addedand the mixture stirred for 10 h at RT followed by removal of thesolvent under reduced pressure. The residue was taken up in 3 mlsaturated NaHCO₃ solution and filtered through a chem elut® cartridge byelution with ethyl acetate. After concentration under reduced pressureand purification by preparative HPLC (C18 reverse phase column, elutionwith a H₂O/MeCN gradient with 0.5% TFA) the fractions containing theproduct were evaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 18 mg MS (ESI+): 484, chloro pattern

Analogously to example 167 the following compounds were prepared by asimilar procedure:

Example Structure MS (ESI+) 168

562, chloro pattern 169

484, chloro pattern 170

499, chloro pattern 171

494, chloro pattern

Example 172N-[1-(2-Chloro-pyrimidin-4-yl)-piperidin-4-ylmethyl]-3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methyl-benzamide

C-[1-(2-Chloro-pyrimidin-4-yl)-piperidin-4-yl]-methylamine

[1-(2-Chloro-pyrimidin-4-yl)-piperidin-4-ylmethyl]-carbamic acidtert-butyl ester (200 mg) was stirred with 50% aqueous trifluoro-aceticacid (5 ml) 24 hours at room temperature. The mixture was evaporated andlyophilized. The product was obtained as its trifluoroacetate salt.

Yield: 300 mg MS: 227.2/229.2 (M+H)⁺.

(ii)N-[1-(2-Chloro-pyrimidin-4-yl)-piperidin-4-ylmethyl]-3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzamide

3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzoic acid (50 mg, 0.15mmol) and triethyl-amine (46.7 mg, 0.46 mmol) were dissolved in 5 ml ofdichloro-methane. After cooling to −15° C. ethyl chloroformate (18.4 mg,0.17 mmol) in 5 ml of dichloro-methane was added and stirred at roomtemperature for 24 hours. The mixture was evaporated and the solid waswashed with dodium bicarbonate solution and water and was dried.

Yield: 37 mg (37%) MS: 533.1/535.1 (M+H)⁺.

Example 173N-[1-(5-Amino-[1,2,4]oxadiazol-3-yl)-piperidin-4-ylmethyl]-3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methyl-benzamide

(1-Cyano-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester

Piperidin-4-ylmethyl-carbamic acid tert-butyl ester (4 g, 18.66 mmol)was suspended in 120 ml of acetonitrile. Dried potassium carbonate(2.837 g, 20.53 mmol) was added. A solution of bromoacetonitrile in(3.72 ml, 5 mmolar solution, 18.66 mmol) was added (argon atmosphere)and the mixture was stirred for 3 hours. After addition of aqueous FeSO₄solution and ethyl acetate, the separated solid was filtered and theorganic layer separated, dried and evaporated.

Yield: 4.04 g (90%) MS: 240.2 (M+H)⁺.(ii) [1-(N-Hydroxycarbamimidoyl)-piperidin-4-ylmethyl]-carbamic acidtert-butyl ester

(1-Cyano-piperidin-4-ylmethyl)-carbamic acid tert-butyl ester (2 g, 8.36mmol), hydroxylamine hydrochloride (3.48 g, 50.14 mmol) andtriethylamine (5.92 g, 58.5 mmol) were stirred in 30 ml of isopropanolat room temperature for 4 hours. The mixture was evaporated. Afteraddition of water (pH4) and ethyl acetate, the organic layer wasseparated and evaporated.

Yield: 1.3 g (57%) MS: 273.2 (M+H)⁺.(iii)[1-(5-Trichloromethyl-[1,2,4]oxadiazol-3-yl)-piperidin-4-ylmethyl]-carbamicacid tert-butyl ester

Trichloroaceticacid anhydride (1.24 g, 4 mmol) was added at 0° C. to asolution of [1-(N-Hydroxycarbamimidoyl)-piperidin-4-ylmethyl]-carbamicacid tert-butyl ester (1 g, 3.67 mmol) in 80 ml of tetrahydro-furan. Thetemperature was raised at room temperature and stirred for 3 hours.After addition of triethylamine (0.74 ml, 7.34 mmol) the mixture washeated at 70° C. for 2 hours and evaporated. The residue was dilutedwith water and extracted with ethyl acetate. The organic layer was driedwith MgSO₄, evaporated and purified by column chromatography (RP18,acetonitrile/water). The product was obtained as its trifluoroacetatesalt.

Yield: 1.07 g (73%) MS: 399.0/401.1 (M+H)⁺.(iv)C-[1-(5-Trichloromethyl-[1,2,4]oxadiazol-3-yl)-piperidin-4-yl]-methylamine;compound with trifluoro-acetic acid

[1-(5-Trichloromethyl-[1,2,4]oxadiazol-3-yl)-piperidin-4-ylmethyl]-carbamicacid tert-butyl ester (500 mg, 1.25 mmol) and 30% aqueoustrifluoro-acetic acid (5 ml) were stirred for 24 hours at roomtemperature. The mixture was evaporated and lyophilised. The productcontains excess of trifluoro-acetic acid.

Yield: 577 mg MS: 298.9/300.9 (M+H)⁺.

3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-N-[1-(5-trichloromethyl-[1,2,4]oxadiazol-3-yl)-piperidin-4-ylmethyl]-benzamide

3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzoic acid (200 mg, 0.615mmol) was dissolved in 5 ml DMF. After cooling to −15° C. HATU (257.34mg, 0.676 mmol) and N-ethylmorpholine (283.3 mg, 2.46 mmol) were added.The mixture was stirred at 0° C. for 15 min. and 30 min. at roomtemperature.C-[1-(5-trichloromethyl-[1,2,4]oxadiazol-3-yl)-piperidin-4-yl]-methylamine;compound with trifluoro-acetic acid (254.4 mg, 0.615 mmol) was added andthe mixture stirred for 1 hour and evaporated under reduced pressure.The residue was dissolved in sodium bicarbonate solution and extractedwith ethyl acetate. The organic layer was dried with MgSO₄ andevaporated. The crude material was used without further purification.

Yield: 250 mg.

N-[1-(5-Amino-[1,2,4]oxadiazol-3-yl)-piperidin-4-ylmethyl]-3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methyl-benzamide;compound with trifluoro-acetic acid

Crude3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methyl-N-[1-(5-trichloromethyl-[1,2,4]oxadiazol-3-yl)-piperidin-4-ylmethyl]-benzamide(250 mg) was dissolved in 60 ml of methanol (containing ammonia, 7molar) in an autoclave at 50 bar pressure and 50° C. for 24 hours. Themixture was evaporated under reduced pressure and purified on RP18 (5μm) (gradient acetonitrile/water (containing 0.1% trifluoro-acetic acid)90:10 to 0:100). The fractions containing the product were evaporatedand lyophilised. The product was obtained as its trifluoroacetate salt.

Yield: 18 mg MS: 504.3/506.3 (M+H)⁺.

Example 1743-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-N-[4-(Pyridin-4-yloxy)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl]-benzamide

4-Cyano-4-trimethylsilanyloxy-piperidine-1-carboxylic acid tert-butylester

4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (6.48 g, 32.52 mmol)was dissolved in 50 ml of tetrahydro-furan. At 0° C. trimethylsilylcyanide (5.08 g, 51.38 mmol) and zink iodide (87 mg, 0.27 mmol) wereadded. The mixture was stirred 3 hours at 0° C. and 3 hours at 60° C.The solid was filtered, the filtrate evaporated and the crude productwas used without further purification.

Yield: 7.54 g MS: 299.1 (M+H)⁺.(ii) 4-Aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butylester

4-Cyano-4-trimethylsilanyloxy-piperidine-1-carboxylic acid tert-butylester (7.5 g) was dissolved in 100 ml of tetrahydro-furan under an argonatmosphere. A solution of lithium aluminium hydride in tetrahydro-furan(30 ml, 1 molar) was dropwise added at 0° C. After stirring for 15 hoursat room temperature, a sodium hydroxide solution (20%) was slowly addedunder cooling. The solid was filtered after dilution with ethyl acetateand the organic layer evaporated. The crude material contains a mixtureof the desired product (MS: 231.2 (M+H)⁺) and the correspondingtrimethylsiliyl ether (MS: 303.1 (M+H)⁺) and was used without furtherpurification.

Yield: 2.1 g.(iii)3-{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzoyl}-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester

3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzoic acid (300 mg, 0.922mmol) and crude 4-aminomethyl-4-hydroxy-piperidine-1-carboxylic acidtert-butyl ester (212.5 mg, 0.922 mmol) was dissolved in 5 ml DMF. Aftercooling to −15° C. HATU (386 mg, 1 mmol) and N-ethylmorpholine (318.9mg, 2.77 mmol) were added. The mixture was stirred at 0° C. for 2 hoursand at room temperature for 15 hours, evaporated and purified on RP18 (5μm) (gradient acetonitrile water 90:10 to 0:100). The fractionscontaining the product were evaporated and lyophilised. The product wasobtained as its trifluoroacetate salt.

Yield: 155 mg (31%) MS: 549.2 (M+H)⁺.(iv){3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methyl-phenyl}-(1-oxa-3,8-diaza-spiro[4.5]dec-3-yl)-methanone

3-{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzoyl}-1-oxa-3,8-diaza-spiro[4.5]decane-8-carboxylicacid tert-butyl ester (41 mg, 0.075 mmol) were stirred with 80% aqueoustrifluoro-acetic acid (2 ml) for 24 hours at room temperature. Themixture was evaporated and lyophilised. The product was obtained as itstrifluoroacetate salt.

Yield: 42 mg (100%) MS: 449.1/451.1 (M+H)⁺.

(v)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-N-[4-(pyridin-4-yloxy)-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl]-benzamide

{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-phenyl}-(1-oxa-3,8-diaza-spiro[4.5]dec-3-yl)-methanone;compound with trifluoro-acetic acid (42 mg, 0.075 mmol),4-Chloro-pyridine; hydrochloride (33.5 mg, 0.22 mmol) and triethyl-amine(37.7 mg, 0.37 mmol) were heated in 10 ml of n-butanol under reflux for7 days. The mixture was evaporated and purified on RP18 (5 μm) (gradientacetonitrile water (containing 0.1% trifluoro-acetic acid) 90:10 to0:100). The fractions containing the product were evaporated andlyophilised. The product was obtained as its trifluoroacetate salt.

Yield: 14 mg (23%) MS: 591.3/593.3 (M+H)⁺.

Example 1753-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-N-{1-[1-(2-oxo-1,2-dihydro-pyrimidin-4-yl)-piperidin-4-yl]-ethyl}-benzamide

N-(1-pyridin-4-yl-ethyl)-formamide

1-pyridin-4-yl-ethanone (24.2 g, 199.77 mmol) and 10 ml of formic acidwere heated to 180° C. and formamide (126 g, 2.797 mol) in 10 ml offormic acid was added within 30 min. The mixture was stirred for 90min., cooled and poured in 100 ml of water. After addition of conc.sodium hydroxide solution until pH13 the product was extracted withdiethyl-ether. The organic layer was dried with MgSO₄ and evaporated.Purification by distillation (165° C./4 mbar) yields pure product.

Yield: 17.9 g (60%) MS: 151.1 (M+H)⁺.(ii) N-(1-piperidin-4-yl-ethyl)-formamide

N-(1-Pyridin-4-yl-ethyl)-formamide (1.86 g, 12.38 mmol) was dissolved in50 ml of acetic acid. After addition of Rh (5% on Al₂O_(3,) 307 mg) themixture was hydrogenated with 10 bar hydrogen and 100° C. for 120 hours.The mixture was evaporated and lyophilised. The crude material was usedwithout purification.

Yield: 2.52 g MS: 157.2 (M+H)⁺.(iii) N-{1-[1-(2-Chloro-pyrimidin-4-yl)-piperidin-4-yl]-ethyl}-formamide

N-(1-Piperidin-4-yl-ethyl)-formamide; compound with acetic acid (350 mg,1.61 mmol), 2,4-dichloro-pyrimidine (265 mg, 1.78 mmol) andethyl-diisopropyl-amine (848 mg, 6.56 mmol) in 20 ml of ethanol wereheated under reflux for 5 hours. The mixture was evaporated and theresidue dissolved in water and extracted with ethyl acetate. The organiclayer was dried with MgSO₄ and evaporated.

Yield: 246 mg (46%) MS: 269.2 (M+H)⁺.

4-[4-(1-Amino-ethyl)-piperidin-1-yl]-1H-pyrimidin-2-one

N-{1-[1-(2-Chloro-pyrimidin-4-yl)-piperidin-4-yl]-ethyl}-formamide (240mg, 0.89 mmol) in 10 ml of 6 N hydrochloric acid was heated under refluxfor 1 hour. The mixture was evaporated and lyophilised.

Yield: 200 mg MS: 223.3 (M+H)⁺.(v)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-N-{1-[1-(2-oxo-1,2-dihydro-pyrimidin-4-yl)-piperidin-4-yl]-ethyl}-benzamide

3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methyl-benzoic acid (50 mg, 0.15mmol) and 4-[4-(1-Amino-ethyl)-piperidin-1-yl]-1H-pyrimidin-2-one;hydrochloride (39.8 mg, 0.15 mmol) was dissolved in 3 ml DMF. Aftercooling to −15° C. HATU (64 mg, 0.17 mmol) and N-ethylmorpholine (53.1mg, 0.46 mmol) were added. The mixture was stirred at 0° C. for 2 hoursand at room temperature for 5 hours, evaporated and purified on RP18 (5μm) (gradient acetonitrile water 90:10 to 0:100). The fractionscontaining the product were evaporated and lyophilised. The product wasobtained as its trifluoroacetate salt.

Yield: 33 mg (40%) MS: 529.3/531.3 (M+H)⁺.

Example 176{4-Bromo-3-[2-(2,4-dichloro-phenyl)-ethoxy]-phenyl}-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanone

0.05 g (0.13 mmol) of 4-Bromo-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoicacid was dissolved in 3 ml of DMF and treated with 0.059 g (0.51 mmol)of NEM and 0.042 g (0.13 mmol) of TOTU and 0.023 g (0.13 mmol) of1-Pyridin-4-ylmethyl-piperazine. The solution was stirred for 16 h atRT. The solvent was removed under reduced pressure, the residue wastaken-up in acetonitrile and the residue was purified by preparativeRP-HPLC eluting with a gradient of 0 to 100% acetonitrile in water(+0.01% trifluoroacetic acid). After lyophilization the product wasobtained as its trifluoroacetate salt.

Yield 4.44 mg MS (ES⁺): m/e=550 (M+H)⁺.

Example 177{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4,5-diethoxy-phenyl}-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanone(S0013313)

3,4-Diethoxy-5-hydroxy-benzoic acid ethyl ester

5 g (25.2 mmol) of 3,4,5-trihydroxy-benzoic acid ethyl ester wasdissolved in 20 ml of DMF and treated at 0° C. with 13.95 g (100.9 mmol)of potassium carbonate and 6.185 g (56.7 mmol) of ethyl bromide. Thesolution was stirred for 16 h at RT. The solvent was removed underreduced pressure, the residue was taken-up in ethyl acetate and thesolution was washed three times with water and twice with saturatedaqueous sodium chloride. The organic phase was dried with magnesiumsulphate, filtered and the solvent was removed under reduced pressure.The residue was chromatographed on silica gel eluting withn-heptane/ethyl acetate (5/1).

Yield 1.2 g. MS (ES⁺): m/e=255 (M+H)⁺.

(ii) 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4,5-diethoxy-benzoic acid ethylester

g (3.93 mmol) of 3,4-Diethoxy-5-hydroxy-benzoic acid ethyl ester wasdissolved in 20 ml of anhydrous tetrahydrofuran. To this solution wasadded 0.83 g (4.33 mmol) of 2-(2,4-Dichlorophenyl)-ethanol, 3.93 g(equivalent to 11.8 mmol PPh₃) of triphenylphosphine derivatizedpolystyrene and 2.05 g (11.8 mmol) of DEAD. The solution was shaken for16 h at RT. The polymer was filtered off and washed with ethyl acetate.The solvent was removed under reduced pressure. The residue was taken-upin ethyl acetate and the solution was washed three times with water andtwice with saturated aqueous sodium chloride. The organic phase wasdried with magnesium sulphate, filtered and the solvent was removedunder reduced pressure. The residue was chromatographed on silica geleluting with ethyl acetate/n-heptane (1/5).

Yield 660 mg. LC-MS (ES+): m/e=427 (M)⁺

(iii) 3-[2-(2,4-Dichlorophenyl)-ethoxy]-4,5-diethoxy-benzoic acid

0.66 g (1.54 mmol) of3-[2-(2,4-Dichlorophenyl)-ethoxy]-4,5-diethoxy-benzoic acid ethyl esterwas dissolved in 6 ml of dioxan. 5 ml of water and 2N aqueous NaOH wasadded to the solution to give a pH of 13. The reaction solution washeated at 60° C. for 4 h and stirred at room temperature for 16 h. Thereaction solution was cooled to 0° C. and concentrated hydrochloric acidwas added to give a pH of 1-2, whereupon the product precipitated fromsolution. The suspension was stirred for 30 min, then the product wasfiltered off and dried under reduced pressure.

Yield 0.571 g. MS (ES⁺): m/e=399 (M⁺).

(iv){3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4,5-diethoxy-phenyl}-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanone

0.05 g (0.13 mmol) of3-[2-(2,4-Dichlorophenyl)-ethoxy]-4,5-diethoxy-benzoic acid wasdissolved in 2 ml of DMF and treated with 0.059 g (0.51 mmol) of NEM and0.041 g (0.13 mmol) of TOTU and 0.022 g (0.13 mmol) of1-pyridin-4-ylmethyl-piperazine. The solution was stirred for 16 h atRT. The solvent was removed under reduced pressure, the residue wastaken-up in acetonitrile and the residue was purified by preparativeRP-HPLC eluting with a gradient of 0 to 100% acetonitrile in water(+0.01% trifluoroacetic acid). After lyophilization the product wasobtained as its trifluoroacetate salt.

Yield 17.8 mg. MS (ES⁺): m/e=558 (M+H)⁺.

Example 1783-[2-(2,4-Dichloro-phenyl)-ethoxy]-4,5-diethoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

0.050 g (0.13 mmol) of3-[2-(2,4-Dichlorophenyl)-ethoxy]-4,5-diethoxy-benzoic acid wasdissolved in 2 ml of DMF and treated with 0.058 g (0.5 mmol) of NEM and0.041 g (0.13 mmol) of TOTU and 0.067 g (0.13 mmol) ofC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetris-trifluoroacetate salt. The solution was stirred for 16 h at RT. Thesolvent was removed under reduced pressure, the residue was taken-up inethyl acetate and the solution was washed twice with saturated aqueoussodium bicarbonate and once with saturated aqueous sodium chloride. Theorganic phase was dried with magnesium sulphate, filtered and thesolvent was removed under reduced pressure. The residue was purified bypreparative RP-HPLC eluting with a gradient of 0 to 100% acetonitrile inwater (+0.01% trifluoroacetic acid). After lyophilization the productwas obtained as its trifluoroacetate salt. Yield 35.3 mg. MS (ES⁺):m/e=572 (M⁺).

Example 1794-Bromo-3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-ethoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide(S0013436)

4-Bromo-3-[2-(2,4-dichlorophenyl)-ethoxy]-5-ethoxy-benzoic acid ethylester

200 mg (0.49 mmol) of4-Bromo-3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-hydroxy-benzoic acid wasdissolved in 5 ml of DMF and treated at 0° C. with 272 mg (1.97 mmol) ofpotassium carbonate and 537 mg (4.93 mmol) of ethyl bromide. Thesolution was stirred for 16 h at RT. The solvent was removed underreduced pressure, the residue was taken-up in ethyl acetate and thesolution was washed three times with water and twice with saturatedaqueous sodium chloride. The organic phase was dried with magnesiumsulphate, filtered and the solvent was removed under reduced pressure.

Yield 219 mg. MS (ES⁺): m/e=463 (M+H⁺).

(ii) 4-Bromo-3-[2-(2,4-dichlorophenyl)-ethoxy]-5-ethoxy-benzoic acid

0.21 g (0.47 mmol) of4-Bromo-3-[2-(2,4-dichlorophenyl)-ethoxy]-5-ethoxy-benzoic acid ethylester was dissolved in 6 ml of dioxan. 6 ml of water and 2N aqueous NaOHwas added to the solution to give a pH of 13. The reaction solution washeated at 60° C. for 4 h and stirred at room temperature for 16 h. Thereaction solution was cooled to 0° C. and concentrated hydrochloric acidwas added to give a pH of 1-2, whereupon the product precipitated fromsolution. The suspension was stirred for 30 min, then the product wasfiltered off and dried under reduced pressure.

Yield 0.175 g. MS (ES⁺): m/e=434 (M⁺).

(iii)4-Bromo-3-[2-(2,4-dichlorophenyl)-ethoxy]-5-ethoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

0.050 g (0.12 mmol) of4-Bromo-3-[2-(2,4-dichlorophenyl)-ethoxy]-5-ethoxy-benzoic acid wasdissolved in 3 ml of DMF and treated with 0.053 g (0.46 mmol) of NEM and0.038 g (0.12 mmol) of TOTU and 0.061 g (0.12 mmol) ofC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetris-trifluoroacetate salt. The solution was stirred for 16 h at RT. Thesolvent was removed under reduced pressure. The residue was purified bypreparative RP-HPLC eluting with a gradient of 0 to 100% acetonitrile inwater (+0.01% trifluoroacetic acid). After lyophilization the productwas obtained as its trifluoroacetate salt.

Yield 42 mg. MS (ES⁺): m/e=608 (M+H⁺).

Example 180{4-Bromo-3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-ethoxy-phenyl}-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanone(S0013437)

0.050 g (0.12 mmol) of4-Bromo-3-[2-(2,4-dichlorophenyl)-ethoxy]-5-ethoxy-benzoic acid wasdissolved in 3 ml of DMF and treated with 0.053 g (0.46 mmol) of NEM and0.038 g (0.12 mmol) of TOTU and 0.020 g (0.12 mmol) of1-Pyridin-4-ylmethyl-piperazine. The solution was stirred for 16 h atRT. The solvent was removed under reduced pressure, the residue wastaken-up in acetonitrile and the residue was purified by preparativeRP-HPLC eluting with a gradient of 0 to 100% acetonitrile in water(+0.01% trifluoroacetic acid). After lyophilization the product wasobtained as its trifluoroacetate salt. Yield 17.8 mg. MS (ES⁺): m/e=594(M+H)⁺.

Example 1814-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide(S0013438)

4-Chloro-3-hydroxy-benzoic acid methyl ester

5 g (29 mmol) of 4-Chloro-3-hydroxy-benzoic acid was suspended in 30 mlof saturated methanolic HCl and stirred at room temperature for 16 h. 20ml of saturated methanolic HCl was added and stirred at room temperaturefor a further 16 h. The solvent was removed under reduced pressure, andthe residue was dried under reduced pressure.

Yield 5.3 g. MS (ES⁺): m/e=187 (M+H)⁺.

(ii) 4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid methylester

2.0 g (10.72 mmol) of 4-Chloro-3-hydroxy-benzoic acid methyl ester wasdissolved in 20 ml of anhydrous tetrahydrofuran. To this solution wasadded 2.25 g (11.79 mmol) of 2-(2,4-Dichlorophenyl)-ethanol, 10.71 g(equivalent to 32.2 mmol PPh₃) of triphenylphosphine derivatizedpolystyrene and 5.6 g (32.2 mmol) of DEAD. The solution was shaken for16 h at RT. The polymer was filtered off and washed with ethyl acetate.The solvent was removed under reduced pressure. The residue was taken-upin ethyl acetate and the solution was washed three times with water andtwice with saturated aqueous sodium chloride. The organic phase wasdried with magnesium sulphate, filtered and the solvent was removedunder reduced pressure. The residue was chromatographed on silica geleluting with ethyl acetate/n-heptane (1/6).

Yield 3 g. LC-MS (ES⁺): m/e=359 (M)⁺

(iii) 4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid

g (2.78 mmol) of 4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoicacid methyl ester was dissolved in 10 ml of dioxan. 5 ml of water and 2Naqueous NaOH was added to the solution to give a pH of 13. The reactionsolution was heated at 60° C. for 4 h and stirred at room temperaturefor 16 h. The reaction solution was cooled to 0° C. and concentratedhydrochloric acid was added to give a pH of 1-2, whereupon the productprecipitated from solution. The suspension was stirred for 30 min, thenthe product was filtered off and dried under reduced pressure.

Yield 0.910 g. MS (ES⁺): m/e=345 (M⁺).

(iv)4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

0.050 g (0.15 mmol) of4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid was dissolvedin 3 ml of DMF and reacted with 0.067 g (0.58 mmol) of NEM and 0.048 g(0.15 mmol) of TOTU and 0.077 g (0.14 mmol) ofC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetris-trifluoroacetate salt. The solution was stirred for 16 h at RT. Thesolvent was removed under reduced pressure. The residue was purified bypreparative RP-HPLC eluting with a gradient of 0 to 100% acetonitrile inwater (+0.01% trifluoroacetic acid). After lyophilization the productwas obtained as its trifluoroacetate salt. Yield 45.7 mg. MS (ES⁺):m/e=518 (M⁺).

Example 182{4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-phenyl}-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanone(S0013439)

0.050 g (0.15 mmol) of4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-benzoic acid was dissolvedin 3 ml of DMF and treated with 0.067 g (0.58 mmol) of NEM and 0.048 g(0.15 mmol) of TOTU and 0.026 g (0.15 mmol) of1-Pyridin-4-ylmethyl-piperazine. The solution was stirred for 16 h atRT. The solvent was removed under reduced pressure. The residue waspurified by preparative RP-HPLC eluting with a gradient of 0 to 100%acetonitrile in water (+0.01% trifluoroacetic acid). Afterlyophilization the product was obtained as its trifluoroacetate salt.

Yield 62.6 mg. MS (ES⁺): m/e=504 (M⁺).

Example 1833-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-isopropoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide(S0013552)

3-Hydroxy-4-isopropoxy-benzoic acid ethyl ester

5 g (27.5 mmol) of 3,4-Dihydroxy-benzoic acid ethyl ester was dissolvedin 110 ml of DMF and treated at 0° C. with 3.8 g (27.5 mmol) ofpotassium carbonate and 3.38 g (27.5 mmol) of isopropyl bromide. Thesolution was stirred for 16 h at RT, then a further 1.014 g (8.3 mmol)of isopropyl bromide was added. The reaction solution was heated at 50°C. for 3 h. The solvent was removed under reduced pressure, the residuewas taken-up in ethyl acetate and the solution was washed three timeswith water and twice with saturated aqueous sodium chloride. The organicphase was dried with magnesium sulphate, filtered and the solvent wasremoved under reduced pressure. The residue was chromatographed onsilica gel eluting with n-heptane/ethyl acetate (5/1).

Yield 2.45 g. MS (ES⁺): m/e=225 (M+H⁺).

(ii) 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-isopropoxy-benzoic acid ethylester

1.5 g (6.69 mmol) of 3-Hydroxy-4-isopropoxy-benzoic acid ethyl ester wasdissolved in 20 ml of anhydrous tetrahydrofuran. To this solution wasadded 1.4 g (7.36 mmol) of 2-(2,4-Dichlorophenyl)-ethanol, 6.7 g(equivalent to 20 mmol PPh₃) of triphenylphosphine derivatizedpolystyrene and 3.5 g (20 mmol) of DEAD. The solution was shaken for 16h at RT. The polymer was filtered off and washed with ethyl acetate. Thesolvent was removed under reduced pressure. The residue was taken-up inethyl acetate and the solution was washed three times with water andtwice with saturated aqueous sodium chloride. The organic phase wasdried with magnesium sulphate, filtered and the solvent was removedunder reduced pressure. The residue was chromatographed on silica geleluting with ethyl acetate/n-heptane (1/6).

Yield 0.77 g. LC-MS (ES⁺): m/e=397 (M)⁺

(iii) 3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-isopropoxy-benzoic acid

0.75 g (1.89 mmol) of3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-isopropoxy-benzoic acid ethyl esterwas dissolved in 15 ml of dioxan. 5 ml of water and 2N aqueous NaOH wasadded to the solution to give a pH of 13. The reaction solution washeated at 60° C. for 4 h and stirred at room temperature for 16 h. Thereaction solution was cooled to 0° C. and concentrated hydrochloric acidwas added to give a pH of 1-2, whereupon the product precipitated fromsolution. The suspension was stirred for 30 min, then the product wasfiltered off and dried under reduced pressure.

Yield 0.630 g. MS (ES⁺): m/e=369 (M⁺).

(iv)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-isopropoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

0.050 g (0.14 mmol) of3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-isopropoxy-benzoic acid wasdissolved in 3 ml of DMF and treated with 0.062 g (0.54 mmol) of NEM and0.044 g (0.14 mmol) of TOTU and 0.072 g (0.14 mmol) ofC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetris-trifluoroacetate salt. The solution was stirred for 16 h at RT. Thesolvent was removed under reduced pressure. The residue was purified bypreparative RP-HPLC eluting with a gradient of 0 to 100% acetonitrile inwater (+0.01% trifluoroacetic acid). After lyophilization the productwas obtained as its trifluoroacetate salt.

Yield 27.9 mg. MS (ES⁺): m/e=542 (M⁺).

Example 184{3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-isopropoxy-phenyl}-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanone

0.050 g (0.14 mmol) of3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-isopropoxy-benzoic acid wasdissolved in 3 ml of DMF and treated with 0.062 g (0.54 mmol) of NEM and0.044 g (0.14 mmol) of TOTU and 0.024 g (0.14 mmol) of1-Pyridin-4-ylmethyl-piperazine. The solution was stirred for 16 h atRT. The solvent was removed under reduced pressure. The residue waspurified by preparative RP-HPLC eluting with a gradient of 0 to 100%acetonitrile in water (+0.01% trifluoroacetic acid). Afterlyophilization the product was obtained as its trifluoroacetate salt.

Yield 44.3 mg. MS (ES⁺): m/e=528 (M⁺).

Example 1857-[2-(2,4-Dichloro-phenyl)-ethoxy]-benzo[1,3]dioxole-5-carboxylic acid(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-amide

7-Hydroxy-benzo[1,3]dioxole-5-carboxylic acid ethyl ester

5 g (25.2 mmol) of 3,4,5-Trihydroxy-benzoic acid ethyl ester wasdissolved in 50 ml of DMF and treated at 0° C. with 13.95 g (101 mmol)of potassium carbonate and 4.39 g (25.2 mmol) of dibromomethane. Thereaction solution was heated at 60° C. for 3 h. The solvent was removedunder reduced pressure, the residue was taken-up in ethyl acetate andthe solution was washed three times with water and twice with saturatedaqueous sodium chloride. The organic phase was dried with magnesiumsulphate, filtered and the solvent was removed under reduced pressure.The residue was chromatographed on silica gel eluting withn-heptane/ethyl acetate (3/1).

Yield 0.45 g. MS (ES⁺): m/e=211 (M+H⁺).

(ii) 7-[2-(2,4-Dichloro-phenyl)-ethoxy]-benzo[1,3]dioxole-5-carboxylicacid ethyl ester.

410 mg (1.95 mmol) of 7-Hydroxy-benzo[1,3]dioxole-5-carboxylic acidethyl ester was dissolved in 20 ml of anhydrous tetrahydrofuran. To thissolution was added 410 mg (2.15 mmol) of 2-(2,4-Dichlorophenyl)-ethanol,1.9 g (equivalent to 5.85 mmol PPh₃) of triphenylphosphine derivatizedpolystyrene and 1.0 g (5.85 mmol) of DEAD. The solution was shaken for16 h at RT. The polymer was filtered off and washed with ethyl acetate.The solvent was removed under reduced pressure. The residue was taken-upin ethyl acetate and the solution was washed three times with water andtwice with saturated aqueous sodium chloride. The organic phase wasdried with magnesium sulphate, filtered and the solvent was removedunder reduced pressure. The residue was chromatographed on silica geleluting with ethyl acetate/n-heptane (1/5).

Yield 0.41 mg. LC-MS (ES⁺): m/e=383 (M)⁺

(iii) 7-[2-(2,4-dichloro-phenyl)-ethoxy]-benzo[1,3]Dioxole-5-carboxylicacid

0.41 g (1.07 mmol) of7-[2-(2,4-Dichloro-phenyl)-ethoxy]-benzo[1,3]dioxole-5-carboxylic acidethyl ester was dissolved in 15 ml of dioxan. 5 ml of water and 2Naqueous NaOH was added to the solution to give a pH of 13. The reactionsolution was heated at 60° C. for 4 h and stirred at room temperaturefor 16 h. The reaction solution was cooled to 0° C. and concentratedhydrochloric acid was added to give a pH of 1-2, whereupon the productprecipitated from solution. The suspension was stirred for 30 min, thenthe product was filtered off and dried under reduced pressure.

Yield 0.35 mg. MS (ES⁺): m/e=355 (M⁺).

(iv) 7-[2-(2,4-Dichloro-phenyl)-ethoxy]-benzo[1,3]dioxole-5-carboxylicacid (3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-amide

0.050 g (0.14 mmol) of7-[2-(2,4-Dichloro-phenyl)-ethoxy]-benzo[1,3]dioxole-5-carboxylic acidwas dissolved in 3 ml of DMF and treated with 0.065 g (0.56 mmol) of NEMand 0.046 g (0.14 mmol) of TOTU and 0.075 g (0.14 mmol) ofC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetris-trifluoroacetate salt. The solution was stirred for 16 h at RT. Thesolvent was removed under reduced pressure. The residue was purified bypreparative RP-HPLC eluting with a gradient of 0 to 100% acetonitrile inwater (+0.01% trifluoroacetic acid). After lyophilization the productwas obtained as its trifluoroacetate salt.

Yield 47.4 mg. MS (ES⁺): m/e=528 (M⁺).

Example 186{7-[2-(2,4-Dichloro-phenyl)-ethoxy]-benzo[1,3]dioxol-5-yl}-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanone

0.050 g (0.14 mmol) of7-[2-(2,4-Dichloro-phenyl)-ethoxy]-benzo[1,3]dioxole-5-carboxylic acidwas dissolved in 3 ml of DMF and treated with 0.065 g (0.56 mmol) of NEMand 0.046 g (0.14 mmol) of TOTU and 0.025 g (0.14 mmol) of1-Pyridin-4-ylmethyl-piperazine. The solution was stirred for 16 h atRT. The solvent was removed under reduced pressure. The residue waspurified by preparative RP-HPLC eluting with a gradient of 0 to 100%acetonitrile in water (+0.01% trifluoroacetic acid). Afterlyophilization the product was obtained as its trifluoroacetate salt.Yield 74.9 mg. MS (ES⁺): m/e=514 (M⁺).

Example 187{4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-phenyl}-[4-(1-oxy-pyridin-4-ylmethyl)-piperazin-1-yl]-methanone

10 mg (0.01 mmol) of{4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-phenyl}-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanonewas dissolved in 0.5 ml of dichloromethane and 3.5 mg (0.01 mmol) of3-chloroperbenzoic acid was added. The solution was allowed to stand for1 h at RT. The solvent was removed under reduced pressure. The residuewas purified by preparative RP-HPLC eluting with a gradient of 0 to 100%acetonitrile in water (+0.01% trifluoroacetic acid). Afterlyophilization the product was obtained as its trifluoroacetate salt.

Yield 5.2 mg. MS (ES⁺): m/e=520 (M⁺).

Example 188(4-Cyclohexylmethyl-piperazin-1-yl)-{3-[2-(2,4-dichloro-phenyl)-ethoxy]-4-methoxy-phenyl}-methanone

3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid

0.050 g (0.15 mmol) of3-[2-(2,4-Dichloro-phenyl)-ethoxy]-4-methoxy-benzoic acid was dissolvedin 3 ml of DMF and treated with 0.067 g (0.59 mmol) of NEM and 0.048 g(0.15 mmol) of TOTU and 0.027 g (0.15 mmol) of1-cyclohexylmethyl-piperazine. The solution was stirred for 16 h at RT.The solvent was removed under reduced pressure. The residue was purifiedby preparative RP-HPLC eluting with a gradient of 0 to 100% acetonitrilein water (+0.01% trifluoroacetic acid). After lyophilization the productwas obtained as its trifluoroacetate salt. Yield 66.7 mg. MS (ES⁺):m/e=505 (M⁺).

The following examples were prepared analogously to example 188:

Example Structure MS (ES+) 189

551 190

555 191

477 192

543 193

531 194

513 195

494 196

534 197

480 198

506

Example 1994-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

4-Chloro-3,5-dihydroxy-benzoic acid methyl ester

10 g (42.9 mmol) of 4-Bromo-3,5-dihydroxy-benzoic acid was suspended in40 ml of NMP and treated with 6.37 g (64.3 mmol) of CuCl. The reactionwas heated at 205° C. for 2 h. The solution was poured into 1 L ofwater. The resulting precipitate was filtered off. The product wasextracted from the resulting solution with ethyl acetate. The organicphase was washed twice with saturated aqueous sodium chloride. Theorganic phase was dried with sodium sulphate, filtered and the solventwas removed under reduced pressure. The residue was dissolve insaturated methanolic HCl and stirred at RT for 16 h. The solvent wasremoved under reduced pressure. The residue was chromatographed onsilica gel eluting with dichloromethane/methanol (10/1).

Yield 3.9 g. MS (ES⁺): m/e=203 (M+H⁺).

(ii) 4-Chloro-3-hydroxy-5-methoxy-benzoic acid methyl ester

3.9 g (19.3 mmol) of 4-Chloro-3,5-dihydroxy-benzoic acid methyl esterwas dissolved in 250 ml of DMF and treated at 0° C. with 8.6 g (62 mmol)of potassium carbonate and 2.72 g (19.2 mmol) of iodomethane. Thereaction solution was stirred at RT for 16 h. The solvent was removedunder reduced pressure, the residue was taken-up in ethyl acetate andthis solution was washed three times with water and twice with saturatedaqueous sodium chloride. The organic phase was dried with sodiumsulphate, filtered and the solvent was removed under reduced pressure.The residue was chromatographed on silica gel eluting withn-heptane/ethyl acetate (5/1).

Yield 1.2 g. MS (ES⁺): m/e=217 (M+H⁺).

(iii) 4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-methoxy-benzoic acidmethyl ester

500 mg (2.31 mmol) of 4-Chloro-3-hydroxy-5-methoxy-benzoic acid methylester was dissolved in 15 ml of anhydrous tetrahydrofuran. To thissolution was added 485 mg (2.54 mmol) of 2-(2,4-Dichlorophenyl)-ethanol,2.3 g (equivalent to 6.92 mmol PPh₃) of triphenylphosphine derivatizedpolystyrene and 1.2 g (6.92 mmol) of DEAD. The solution was shaken for16 h at RT. The polymer was filtered off and washed with ethyl acetate.The solvent was removed under reduced pressure. The residue waschromatographed on silica gel eluting with ethyl acetate/n-heptane(1/5).

Yield 0.66 g. LC-MS (ES⁺): m/e=389 (M)⁺

(iii) 4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-methoxy-benzoic acid

0.51 g (1.31 mmol) of4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-methoxy-benzoic acidmethyl ester was dissolved in 15 ml of dioxan. 5 ml of water and 2Naqueous NaOH was added to the solution to give a pH of 13. The reactionsolution was heated at 60° C. for 4 h and stirred at room temperaturefor 16 h. The reaction solution was cooled to 0° C. and concentratedhydrochloric acid was added to give a pH of 1-2, whereupon the productprecipitated from solution. The suspension was stirred for 30 min, thenthe product was filtered off and dried under reduced pressure.

Yield 0.46 g. MS (ES⁺): m/e=375 (M⁺).

(iv)4-Chloro-3-[2-(2,4-Dichloro-phenyl)-ethoxy]-5-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

0.050 g (0.13 mmol) of4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-methoxy-benzoic acid wasdissolved in 3 ml of DMF and treated with 0.061 g (0.53 mmol) of NEM and0.043 g (0.13 mmol) of TOTU and 0.071 g (0.13 mmol) ofC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetris-trifluoroacetate salt. The solution was stirred for 16 h at RT. Thesolvent was removed under reduced pressure. The residue was purified bypreparative RP-HPLC eluting with a gradient of 0 to 100% acetonitrile inwater (+0.01% trifluoroacetic acid). After lyophilization the productwas obtained as its trifluoroacetate salt.

Yield 24.8 mg. MS (ES⁺): m/e=550 (M+H⁺).

Example 200{4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-methoxy-phenyl}-(4-pyridin-4-ylmethyl-piperazin-1-yl)-methanone

0.050 g (0.13 mmol) of4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-methoxy-benzoic acid wasdissolved in 3 ml of DMF and treated with 0.061 g (0.53 mmol) of NEM and0.043 g (0.13 mmol) of TOTU and 0.024 g (0.13 mmol) of1-Pyridin-4-ylmethyl-piperazine. The solution was stirred for 16 h atRT. The solvent was removed under reduced pressure. The residue waspurified by preparative RP-HPLC eluting with a gradient of 0 to 100%acetonitrile in water (+0.01% trifluoroacetic acid). Afterlyophilization the product was obtained as its trifluoroacetate salt.

Yield 56.8 mg. MS (ES⁺): m/e=536 (M+H⁺).

Example 2014-Chloro-3-[2-(4-methoxy-phenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide(S0100717)

4-Chloro-3-[2-(4-methoxy-phenyl)-ethoxy]-benzoic acid methyl ester

g (5.36 mmol) of 4-Chloro-3-hydroxy-benzoic acid methyl ester wasdissolved in 40 ml of anhydrous tetrahydrofuran. To this solution wasadded 0.897 g (5.9 mmol) of 2-(4-Methoxy-phenyl)-ethanol, 5.35 g(equivalent to 16.1 mmol PPh₃) of triphenylphosphine derivatizedpolystyrene and 2.80 g (16.1 mmol) of DEAD. The solution was shaken for16 h at RT. The polymer was filtered off and washed with ethyl acetate.The solvent was removed under reduced pressure. The residue was taken-upin ethyl acetate and the solution was washed three times with water andtwice with saturated aqueous sodium chloride. The organic phase wasdried with magnesium sulphate, filtered and the solvent was removedunder reduced pressure. The residue was chromatographed on silica geleluting with ethyl acetate/n-heptane (1/5).

Yield 1.27 mg. LC-MS (ES⁺): m/e=321 (M)⁺

(ii) 4-Chloro-3-[2-(4-methoxy-phenyl)-ethoxy]-benzoic acid

1.27 g (3.96 mmol) of 4-Chloro-3-[2-(4-methoxy-phenyl)-ethoxy]-benzoicacid methyl ester was dissolved in 15 ml of dioxan. 5 ml of water and 2Naqueous NaOH was added to the solution to give a pH of 13. The reactionsolution was heated at 60° C. for 2 h and stirred at room temperaturefor 16 h. The reaction solution was cooled to 0° C. and concentratedhydrochloric acid was added to give a pH of 1-2, whereupon the productprecipitated from solution. The suspension was stirred for 30 min, thenthe product was filtered off and dried under reduced pressure.

Yield 1.10 mg. MS (ES⁺): m/e=307 (M+H⁺).

(iii)4-Chloro-3-[2-(4-methoxy-phenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

0.050 g (0.16 mmol) of 4-Chloro-3-[2-(4-methoxy-phenyl)-ethoxy]-benzoicacid was dissolved in 3 ml of DMF and treated with 0.188 g (1.63 mmol)of NEM and 0.054 g (0.16 mmol) of TOTU and 0.087 g (0.16 mmol) ofC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetris-trifluoroacetate salt. The solution was stirred for 16 h at RT. Thesolvent was removed under reduced pressure. The residue was purified bypreparative RP-HPLC eluting with a gradient of 0 to 100% acetonitrile inwater (+0.01% trifluoroacetic acid). After lyophilization the productwas obtained as its trifluoroacetate salt. Yield 40.1 mg.

MS (ES⁺): m/e=480 (M⁺).

Example 2024-Chloro-3-[2-(4-chloro-phenyl)-ethoxy]-5-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

This compound was prepared analogously to Example 199.

Yield 44.4 mg. MS (ES⁺): m/e=514 (M⁺).

Example 2034-Chloro-3-[2-(4-chloro-phenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

4-Chloro-3-[2-(4-chloro-phenyl)-ethoxy]-benzoic acid methyl ester

g (5.36 mmol) of 4-Chloro-3-hydroxy-benzoic acid methyl ester wasdissolved in 40 ml of anhydrous tetrahydrofuran. To this solution wasadded 0.923 g (5.9 mmol) of 2-(4-chloro-phenyl)-ethanol, 5.35 g(equivalent to 16.1 mmol PPh₃) of triphenylphosphine derivatizedpolystyrene and 2.80 g (16.1 mmol) of DEAD. The solution was shaken for16 h at RT. The polymer was filtered off and washed with ethyl acetate.The solvent was removed under reduced pressure. The residue was taken-upin ethyl acetate and the solution was washed three times with water andtwice with saturated aqueous sodium chloride. The organic phase wasdried with magnesium sulphate, filtered and the solvent was removedunder reduced pressure. The residue was chromatographed on silica geleluting with ethyl acetate/n-heptane (1/5). Yield 1.6 g. LC-MS (ES⁺):m/e=325 (M)⁺

4-Chloro-3-[2-(4-chloro-phenyl)-ethoxy]-benzoic acid

1.6 g (4.94 mmol) of 4-Chloro-3-[2-(4-chloro-phenyl)-ethoxy]-benzoicacid methyl ester was dissolved in 15 ml of dioxan. 5 ml of water and 2Naqueous NaOH was added to the solution to give a pH of 13. The reactionsolution was heated at 60° C. for 2 h. The reaction solution was cooledto 0° C. and concentrated hydrochloric acid was added to give a pH of1-2, whereupon the product precipitated from solution. The suspensionwas stirred for 30 min, then the product was filtered off and driedunder reduced pressure.

Yield 1.21 g. MS (ES⁺): m/e=311 (M⁺).

(iii)4-Chloro-3-[2-(4-chloro-phenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

0.050 g (0.16 mmol) of 4-Chloro-3-[2-(4-chloro-phenyl)-ethoxy]-benzoicacid was dissolved in 3 ml of DMF and treated with 0.185 g (1.61 mmol)of NEM and 0.054 g (0.16 mmol) of TOTU and 0.087 g (0.16 mmol) ofC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetris-trifluoroacetate salt. The solution was stirred for 16 h at RT. Thesolvent was removed under reduced pressure. The residue was purified bypreparative RP-HPLC eluting with a gradient of 0 to 100% acetonitrile inwater (+0.01% trifluoroacetic acid). After lyophilization the productwas obtained as its trifluoroacetate salt.

Yield 44 mg. MS (ES⁺): m/e=484 (M⁺).

The following examples were prepared analogously to example 203:

Example Structure MS (ES+) 204

528 205

468 206

464 207

502 208

475 209

484 210

480 211

493

Example 2123-[2-(4-Chloro-phenyl)-ethoxy]-4-fluoro-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

4-Fluoro-3-hydroxy-benzoic acid methyl ester

5.16 g (33 mmol) of 4-Fluoro-3-hydroxy-benzoic acid was suspended in 150ml of saturated methanolic HCl and stirred at room temperature for 16 h.The solvent was removed under reduced pressure, and the residue wasdried under reduced pressure.

Yield 5.5 g. MS (ES⁺): m/e=171 (M+H)⁺.

(ii) 3-[2-(4-Chloro-phenyl)-ethoxy]-4-fluoro-benzoic acid methyl ester

0.5 g (2.94 mmol) of 4-Fluoro-3-hydroxy-benzoic acid methyl ester wasdissolved in 30 ml of anhydrous tetrahydrofuran. To this solution wasadded 0.506 g (3.23 mmol) of 2-(4-chloro-phenyl)-ethanol, 2.93 g(equivalent to 8.8 mmol PPh₃) of triphenylphosphine derivatizedpolystyrene and 1.53 g (8.8 mmol) of DEAD. The solution was shaken for16 h at RT. The polymer was filtered off and washed withtetrahydrofuran. The solvent was removed under reduced pressure. Theresidue was taken-up in ethyl acetate/n-heptane (1/5) and the insolubleresidue was removed by filtration. The solvent was removed under reducedpressure. The residue was chromatographed on silica gel eluting withethyl acetate/n-heptane (1/5).

Yield 0.75 g. LC-MS (ES⁺): m/e=309 (M+H)⁺

(iii) 3-[2-(4-Chloro-phenyl)-ethoxy]-4-fluoro-benzoic acid

0.75 g (2.43 mmol) of 3-[2-(4-Chloro-phenyl)-ethoxy]-4-fluoro-benzoicacid methyl ester was dissolved in 25 ml of dioxan. 5 ml of water and 2Naqueous NaOH was added to the solution to give a pH of 13. The reactionsolution was heated at 60° C. for 2 h. The reaction solution was cooledto 0° C. and concentrated hydrochloric acid was added to give a pH of1-2, whereupon the product precipitated from solution. The suspensionwas stirred for 30 min, then the product was filtered off and driedunder reduced pressure.

Yield 0.64 g. MS (ES⁺): m/e=295 (M+H⁺).

(iv)3-[2-(4-Chloro-phenyl)-ethoxy]-4-fluoro-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

0.053 g (0.18 mmol) of 3-[2-(4-Chloro-phenyl)-ethoxy]-4-fluoro-benzoicacid was dissolved in 2 ml of DMF and treated with 0.206 g (1.8 mmol) ofNEM and 0.059 g (0.18 mmol) of TOTU and 0.075 g (0.18 mmol) ofC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminebis-trifluoroacetate salt. The solution was stirred for 16 h at RT. Thesolvent was removed under reduced pressure. The residue was purified bypreparative RP-HPLC eluting with a gradient of 0 to 100% acetonitrile inwater (+0.01% trifluoroacetic acid). After lyophilization the productwas obtained as its trifluoroacetate salt. Yield 42 mg.

MS (ES⁺): m/e=468 (M⁺).

The following examples were prepared analogously to example 212:

Example Structure MS (ES+) 213

512 214

452 215

485 216

459 217

447 218

468 219

464 220

477 221

448

Example 2224-Chloro-3-[2-(4-chloro-phenyl)-ethoxy]-5-methoxy-N-(2′-methyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

This compound was prepared analogously to Example 202, usingC-(2′-Methyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetrifluoroacetate salt.

Yield 62 mg. MS (ES⁺): m/e=528 (M⁺).

Example 2234-Chloro-3-[2-(4-chloro-phenyl)-ethoxy]-N-(2′-methyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

This compound was prepared analogously to Example 203, usingC-(2′-Methyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetrifluoroacetate salt.

Yield 106 mg. MS (ES⁺): m/e=498 (M⁺).

Example 2244-Bromo-3-[2-(4-chloro-phenyl)-ethoxy]-5-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

This compound was prepared analogously to Example 20.

Yield 88 mg. MS (ES⁺): m/e=558 (M⁺).

Example 2254-Bromo-3-[2-(4-chloro-phenyl)-ethoxy]-5-methoxy-N-(2′-methyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

This compound was prepared analogously to Example 224, usingC-(2′-Methyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetrifluoroacetate salt.

Yield 86 mg. MS (ES⁺): m/e=572 (M⁺).

Example 2265-[2-(2,4-Dichlorophenyl)-ethoxy]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-isophthalamicacid

0.2 g (0.56 mmol) of 5-[2-(2,4-Dichlorophenyl)-ethoxy]-isophthalic acidwas dissolved in 25 ml of DMF and treated with 0.649 g (5.63 mmol) ofNEM and 0.277 g (0.84 mmol) of TOTU and 0.215 g (1.13 mmol) ofC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylamine. Thesolution was stirred for 16 h at RT. The solvent was removed underreduced pressure. The residue was purified by preparative RP-HPLCeluting with a gradient of 0 to 100% acetonitrile in water (+0.01%trifluoroacetic acid). After lyophilization the product was obtained asits trifluoroacetate salt.

Yield 65 mg. MS (ES⁺): m/e=528 (M⁺).

Example 2275-[2-(2,4-Dichloro-phenyl)-ethoxy]-N,N′-bis-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-isophthalamide

0.2 g (0.56 mmol) of 5-[2-(2,4-Dichlorophenyl)-ethoxy]-isophthalic acidwas dissolved in 25 ml of DMF and treated with 0.649 g (5.63 mmol) ofNEM and 0.277 g (0.84 mmol) of TOTU and 0.215 g (1.13 mmol) ofC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylamine. Thesolution was stirred for 16 h at RT. The solvent was removed underreduced pressure. The residue was purified by preparative RP-HPLCeluting with a gradient of 0 to 100% acetonitrile in water (+0.01%trifluoroacetic acid). After lyophilization the product was obtained asits trifluoroacetate salt.

Yield 4 mg. MS (ES⁺): m/e=701 (M⁺).

Example 2284-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-methoxy-N-(1′-oxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

This compound was prepared analogously to Example 199, usingC-(1′-Oxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetrifluoroacetate salt.

Yield 12 mg. MS (ES⁺): m/e=565 (M⁺).

Example 2294-Chloro-3-[2-(4-chloro-phenyl)-ethoxy]-5-methoxy-N-(1′-oxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

This compound was prepared analogously to Example 202, usingC-(1′-Oxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetrifluoroacetate salt.

Yield 8.7 mg. MS (ES⁺): m/e=530 (M⁺).

Example 2304-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-N-(1′-oxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

This compound was prepared analogously to Example 281, usingC-(1′-Oxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetrifluoroacetate salt.

Yield 11 mg. MS (ES⁺): m/e=535 (M⁺).

Example 2314-Chloro-3-[2-(4-chloro-phenyl)-ethoxy]-N-(1′-oxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

This compound was prepared analogously to Example 203, usingC-(1′-Oxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetrifluoroacetate salt.

Yield 16 mg. MS (ES⁺): m/e=500 (M⁺).

Example 2325-[2-(2,4-Dichloro-phenyl)-ethoxy]-N,N-diethyl-N′-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-isophthalamide

5-[2-(2,4-Dichloro-phenyl)-ethoxy]-N,N-diethyl-isophthalamic acid

0.5 g (1.41 mmol) of 5-[2-(2,4-Dichlorophenyl)-ethoxy]-isophthalic acidwas dissolved in 5 ml of DMF and treated with 0.648 g (5.63 mmol) of NEMand 0.461 g (1.41 mmol) of TOTU and 0.103 g (1.41 mmol) of diethylamine.The solution was stirred for 16 h at RT. The compound was purified bypreparative RP-HPLC eluting with a gradient of 0 to 100% acetonitrile inwater (+0.01% trifluoroacetic acid). After lyophilization the productwas obtained as its trifluoroacetate salt.

Yield 163 mg. MS (ES⁺): m/e=410 (M⁺).

(ii):5-[2-(2,4-Dichloro-phenyl)-ethoxy]-N,N-diethyl-N′-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-isophthalamide

0.05 g (0.12 mmol) of5-[2-(2,4-Dichloro-phenyl)-ethoxy]-N,N-diethyl-isophthalamic acid wasdissolved in 1 ml of DMF and treated with 0.140 g (1.22 mmol) of NEM and0.04 g (0.12 mmol) of TOTU and 0.051 g (0.12 mmol) ofC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylamine. Thesolution was stirred for 16 h at RT. The compound was purified bypreparative RP-HPLC eluting with a gradient of 0 to 100% acetonitrile inwater (+0.01% trifluoroacetic acid). After lyophilization the productwas obtained as its trifluoroacetate salt.

Yield 20 mg. MS (ES⁺): m/e=583 (M⁺).

Example 2333-[(2,4-Dichloro-benzylamino)-methyl]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

3-[(2,4-Dichloro-benzylamino)-methyl]-benzoic acid methyl ester

g (5.68 mmol) of 2,4-dichlorobenzylamine was dissolved in 20 ml ofdichloromethane and treated with 2.94 g (22.7 mmol) ofdiisopropylethylamine and 1.43 g (6.25 mmol) of 3-bromomethyl-benzoicacid methyl ester. The solution was stirred for 16 h at RT. The solventwas removed under reduced pressure. The residue was chromatographed onsilica gel eluting with ethyl acetate/n-heptane (1/4).

Yield 990 mg. MS (ES⁺): m/e=324 (M⁺).

(ii)3-{[tert-Butoxycarbonyl-(2,4-dichloro-benzyl)-amino]-methyl}-benzoicacid methyl ester

0.98 g (3.02 mmol) of 3-[(2,4-Dichloro-benzylamino)-methyl]-benzoic acidmethyl ester was dissolved in 20 ml of dioxan and treated with 0.659 g(3.02 mmol) of di-tert-butyl pyrocarbonate. The solution was stirred for16 h at RT. The solvent was removed under reduced pressure.

Yield 1.35 g. MS (ES⁺): m/e=368 (M-tBu⁺).

(iii)3-{[tert-Butoxycarbonyl-(2,4-dichloro-benzyl)-amino]-methyl}-benzoicacid

0.85 g (2.00 mmol) of3-{[tert-Butoxycarbonyl-(2,4-dichloro-benzyl)-amino]-methyl}-benzoicacid methyl ester was dissolved in 20 ml of dioxan. 5 ml of water and 2Naqueous NaOH was added to the solution to give a pH of 13. The reactionsolution was stirred for 5 h then poured into water. The resultingsolution was cooled to 0° C. and concentrated hydrochloric acid wasadded to give a pH of 3. The product was extracted 3 times with ethylacetate. The organic phase was dried over magnesium sulphate, filteredand the solvent was removed under reduced pressure.

Yield 0.77 g. MS (ES⁺): m/e=354 (M-tBu⁺).

(iv)(2,4-Dichloro-benzyl)-{3-[(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-carbamoyl]-benzyl}-carbamicacid tert-butyl ester

0.15 g (0.37 mmol) of3-{[tert-Butoxycarbonyl-(2,4-dichloro-benzyl)-amino]-methyl}-benzoicacid was dissolved in 2 ml of DMF and treated with 0.42 g (3.7 mmol) ofNEM and 0.12 g (0.37 mmol) of TOTU and 0.195 g (0.37 mmol) ofC-(3,4,5,6-Tetrahydro-2H-[1,4′]bipyridinyl-4-yl)-methylaminetrifluoroacetate salt. The solution was stirred for 3 h at RT. Thecompound was purified by preparative RP-HPLC eluting with a gradient of0 to 100% acetonitrile in water (+0.01% trifluoroacetic acid). Afterlyophilization the product was obtained as its trifluoroacetate salt.

Yield 128 mg. MS (ES⁺): m/e=583 (M⁺).

3-[(2,4-Dichloro-benzylamino)-methyl]-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

60 mg (0.1 mmol) of(2,4-Dichloro-benzyl)-{3-[(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-carbamoyl]-benzyl}-carbamicacid tert-butyl ester was dissolved in dichloromethane/TFA (1/1) andstirred for 45 min at RT. The solvent was removed under reduced pressureand the residue was dissolve in acetonitrile/water. After lyophilizationthe product was obtained as its trifluoroacetate salt.

Yield 44 mg. MS (ES⁺): m/e=483 (M⁺).

Example 234[4-(2-{2-Chloro-5-[(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-carbamoyl]-phenoxy}-ethyl)-phenyl]-carbamicacid tert-butyl ester (S0103893)

[4-(2-Hydroxy-ethyl)-phenyl]-carbamic acid tert-butyl ester

5 g (36.4 mmol) of 2-(4-Amino-phenyl)-ethanol was dissolved in 25 ml ofdioxan and treated with 7.95 g (36.4 mmol) of di-tert-butylpyrocarbonate. The solution was stirred for 16 h at RT. The solvent wasremoved under reduced pressure.

Yield 8.5 g. MS (ES⁺): m/e=238 (M+H⁺).

(ii)[4-(2-{2-Chloro-5-[(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-carbamoyl]-phenoxy}-ethyl)-phenyl]-carbamicacid tert-butyl ester

This compound was prepared analogously to Example 203.

Yield 65 mg. MS (ES⁺): m/e=565 (M⁺).

Example 235[4-(2-{2-Fluoro-5-[(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-carbamoyl]-phenoxy}-ethyl)-phenyl]-carbamicacid tert-butyl ester

This compound was prepared analogously to Example 212.

Yield 62 mg. MS (ES⁺): m/e=548 (M⁺).

Example 2363-[2-(4-Amino-phenyl)-ethoxy]-4-chloro-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

62 mg (0.1 mmol) of[4-(2-{2-Chloro-5-[(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-carbamoyl]-phenoxy}-ethyl)-phenyl]-carbamicacid tert-butyl ester was dissolved in dichloromethane/TFA (1/1) andstirred for 30 min at RT. The solvent was removed under reduced pressureand the residue was dissolve in acetonitrile/water. After lyophilizationthe product was obtained as its trifluoroacetate salt.

Yield 36 mg. MS (ES⁺): m/e=465 (M+H⁺).

Example 2373-[2-(4-Amino-phenyl)-ethoxy]-4-fluoro-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

59 mg (0.1 mmol) of[4-(2-{2-Fluoro-5-[(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-carbamoyl]-phenoxy}-ethyl)-phenyl]-carbamicacid tert-butyl ester was dissolved in dichloromethane/TFA (1/1) andstirred for 30 min at RT. The solvent was removed under reduced pressureand the residue was dissolve in acetonitrile/water. After lyophilizationthe product was obtained as its trifluoroacetate salt.

Yield 44 mg. MS (ES⁺): m/e=449 (M+H⁺).

Example 2383-[2-(2,4-Dichloro-phenyl)-ethoxy]-5-methoxy-4-methyl-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

3,5-Dihydroxy-4-methyl-benzoic acid methyl ester

4.8 g (28.6 mmol) of 3,5-Dihydroxy-4-methyl-benzoic acid was suspendedin 100 ml of saturated methanolic HCl and stirred at room temperaturefor 16 h. The solvent was removed under reduced pressure, and theresidue was dried under reduced pressure.

Yield 5.1 g. MS (ES⁻): m/e=181 (M)⁻.

(ii) 3-Hydroxy-5-methoxy-4-methyl-benzoic acid methyl ester

5.1 g (28.2 mmol) of 3,5-Dihydroxy-4-methyl-benzoic acid methyl esterwas dissolved in 100 ml of DMF and treated at 0° C. with 7.8 g (56.4mmol) of potassium carbonate and 4.0 g (28.2 mmol) of methyl iodide. Thesolution was stirred for 16 h at RT. The solvent was removed underreduced pressure, the residue was taken-up in ethyl acetate and thesolution was washed three times with water and twice with saturatedaqueous sodium chloride. The organic phase was dried with magnesiumsulphate, filtered and the solvent was removed under reduced pressure.The compound was purified by preparative RP-HPLC eluting with a gradientof 0 to 100% acetonitrile in water (+0.01% trifluoroacetic acid).

Yield 0.3 g. MS (ES⁻): m/e=194 (M⁻).

(iii)3-[2-(2,4-Dichloro-phenyl)-ethoxy]-5-methoxy-4-methyl-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

This compound was prepared analogously to Example 199.

Yield 39 g. MS (ES⁺): m/e=528 (M⁺).

Example Structure MS (ES+) 239

450 240

446 241

446 242

500 243

500

Example 2443-[2-(4-Cyano-phenyl)-ethoxy]-4-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide

This compound was prepared analogously to Example 139.

Yield 12 g. MS (ES⁺): m/e=471.

Pharmacological Testing

The ability of the compounds of the formula I to inhibit factor Xa orfactor VIIa or other enzymes like thrombin, plasmin, or trypsin can beassessed by determining the concentration of the compound of the formulaI that inhibits enzyme activity by 50%, i. e. the IC₅₀ value, which isrelated to the inhibition constant Ki. Purified enzymes are used inchromogenic assays. The concentration of inhibitor that causes a 50%decrease in the rate of substrate hydrolysis is determined by linearregression after plotting the relative rates of hydrolysis (compared tothe uninhibited control) versus the log of the concentration of thecompound of formula I. For calculating the inhibition constant Ki, theIC₅₀ value is corrected for competition with substrate using the formulaKi=IC ₅₀/{1+(substrate concentration/Km)}

wherein Km is the Michaelis-Menten constant (Chen and Prusoff, Biochem.Pharmacol. 22 (1973), 3099-3108; I. H. Segal, Enzyme Kinetics, 1975,John Wiley & Sons, New York, 100-125; which are incorporated herein byreference).

Factor Xa Assay

In the assay for determining the inhibition of factor Xa activityTBS-PEG buffer (50 mM Tris-HCl, pH 7.8, 200 mM NaCl, 0.05% (w/v)PEG-8000, 0.02% (w/v) NaN₃) was used. The IC₅₀ was determined bycombining in appropriate wells of a Costar half-area microtiter plate 25μl human factor Xa (Enzyme Research Laboratories, Inc.; South Bend,Ind.) in TBS-PEG; 40 μl 10% (v/v) DMSO in TBS-PEG (uninhibited control)or various concentrations of the compound to be tested diluted in 10%(v/v) DMSO in TBS-PEG; and substrate S-2765(N(α)-benzyloxycarbonyl-D-Arg-Gly-L-Arg-p-nitroanilide; Kabi Pharmacia,Inc.; Franklin, Ohio) in TBS-PEG.

The assay was performed by pre-incubating the compound of formula I plusenzyme for 10 min. Then the assay was initiated by adding substrate toobtain a final volume of 100 μl. The initial velocity of chromogenicsubstrate hydrolysis was measured by the change in absorbance at 405 nmusing a Bio-tek Instruments kinetic plate reader (Ceres UV900HDi) at 25°C. during the linear portion of the time course (usually 1.5 min afteraddition of substrate). The enzyme concentration was 0.5 nM andsubstrate concentration was 140 μM.

b) Factor VIIa Assay

The inhibitory activity towards factor VIIa/tissue factor activity wasdetermined using a chromogenic assay essentially as described previously(J. A. Ostrem et al., Biochemistry 37 (1998) 1053-1059, which isincorporated herein by reference). Kinetic assays were conducted at 25°C. in half-area microtiter plates (Costar Corp., Cambridge, Mass.) usinga kinetic plate reader (Molecular Devices Spectramax 250). A typicalassay consisted of 25 μl human factor VIIa and TF (5 nM and 10 nM,respective final concentration) combined with 40 μl of inhibitordilutions in 10% DMSO/TBS-PEG buffer (50 mM Tris, 15 mM NaCl, 5 mMCaCl₂, 0.05% PEG 8000, pH 8.15). Following a 15 minute preincubationperiod, the assay was initiated by the addition of 35 μl of thechromogenic substrate S-2288 (D-Ile-pro-Arg-p-nitroanilide, PharmaciaHepar Inc., 500 μM final concentration). The results (inhibitionconstants Ki (FXa) for inhibition of factor Xa) are shown in Table 1.

TABLE 1 Example Ki(FXa) [μM]  1 0.600  2 1.540  3 5.410  4 0.298  50.167  6 0.050  7 2.820  8 0.106  9 0.306  10 0.061  11 1.378  12 3.005 13 1.412  14 2.184  15 2.221  16 4.219  17 0.407  18 6.200  19 0.095 20 0.020  24 1.128  28 0.960  31 9.340  32 0.970  54 6.515  55 0.650 56 4.327  57 6.217  60 1.051  61 0.057  66 1.484  67 0.018  68 3.040 77 0.076  78 0.037  79 0.029  80 0.050  81 0.241  83 0.125  84 4.883 85 0.304  86 0.026  87 0.070  88 0.140  89 0.044  91 1.393  92 0.028 93 0.188  94 0.760  95 29.734  97 3.497  99 3.709 100 0.298 101 0.057102 0.636 117 0.588 118 0.316 119 1763 120 0.048 121 0.075 128 40.95 12925.18 132 0.054 133 0.020 134 0.037 140 69.50 143 38.79 144 0.041 1450.591 165 0.950 166 0.110 167 0.277 168 0.024 169 0.277 170 1.796 1710.130 172 6.450 176 0.365 177 0.226 178 0.263 179 0.086 180 0.255 1810.041 182 0.312 183 0.233 184 0.617 185 0.039 186 0.401 187 0.964 1956.737 196 4.265 197 6.028 198 5.004 199 0.01 200 0.108 201 0.314 2020.025 203 0.013 204 0.036 205 0.102 206 0.124 207 0.068 208 1.552 2091.931 210 2.494 212 0.040 213 0.071 214 0.203 215 0.059 216 4.605 2170.206 218 0.712 219 3.348 221 0.307 222 0.072 223 0.044 224 0.020 2250.065 226 0.082 227 0.058 228 0.220 229 0.285 230 0.649 231 0.227 2320.192 233 0.275 234 4.531 236 0.420 237 1.554 238 0.013 239 3.839 2401.345 241 2.168 242 2.939

1. A compound of formula I,R⁰—Q—X—Q′—W—U—V—G—M  (I) wherein: R⁰ is phenyl, wherein phenyl isunsubstituted or mono- or disubstituted independently of one another byR², or pyridyl, wherein pyridyl is unsubstituted or mono-, disubstitutedindependently of one another by R²; Q is a direct bond; X is ethylene;Q′ is —O—; W is phenyl or pyridyl, wherein W is unsubstituted or mono-,di- or trisubstituted independently of one another by R¹; U is—(CH₂)_(m)—C(O)—NR¹⁰—(CH₂)_(n), wherein n is zero, 1 or 2, m is zero or1, provided that Q′ and U are in a 1,3-substitution relationship withrespect to each other and the 2-position is unsubstituted; V istetrahydropuridine, pyridine, or phenyl wherein said groups areunsubstituted or mono-, di- or trisubstituted independently of oneanother by R¹⁴; G is a direct bond, —(CH₂)_(m),—(CH₂)_(m)—C(O)—NR¹⁰—(CH₂)_(n), —(CH₂)_(m)—C(O)—(CH₂)_(n),—(CH₂)_(m)—NR¹⁰—C(O)—^(NR10—)(CH₂)_(n), —(CH₂)_(m)—NR10—C(O)—(CH₂)_(n),—(CH₂)_(m)—SO₂—NR¹⁰—(CH₂)_(n) or —(CH₂)_(m)—NR¹⁰—SO₂—(CH₂)_(n), M is ahydrogen atom, —(C₁-C₄)-alkyl, wherein alkyl is unsubstituted or mono-,di- or trisubstituted independently of one another by R¹⁴, —C(O)—NR⁴R⁵,or a residue selected from the group consisting of pyridine and phenyl,wherein R¹, R², and R³ independent from each other are hydrogen, F, Cl,—O—CH₃, —CH₃, —C(O)—N(CH₂-CH₃)₂, —C(O)—NH₂, or—C(O)—NH—CH₂-piperidine-pyridine; R⁴ and R⁵ are independently of oneanother identical or different and are hydrogen atom, —(C₁-C₆)-alkyl,wherein alkyl is unsubstituted or mono-, di- or trisubstitutedindependently of one another by R¹³, —(C₆-C₁₄)-phenyl-(C₁-C₄)-alkyl-,wherein alkyl and phenyl independently from one another areunsubstituted or mono-, di- or trisubstituted by R¹³, —(C₆-C₁₄)-phenyl-,wherein phenyl is unsubstituted or mono-, di- or trisubstitutedindependently of one another by R¹³; R¹⁰ is hydrogen atom or—(C₁-C₄)-alkyl; R¹³ is halogen, —NO₂, —CN, —OH, —(C₁-C₈)-alkyl,—(C₁-C₈)-alkyloxy, —CF₃, —C(O)—NH₂, —NH₂ or the residue V—G—M, whereinV, G and M are as defined above; R¹⁴ is halogen, —OH, —NR⁴R⁵, ═O,—(C₁-C₄)-alkyl, —(C₁-C₄)-alkoxyl, —C(O)—OH, —CN, —C(O)—O—(C₁-C₄)-alkyl,—C(O)—NR⁴R⁵, —(C₁-C₈)-alkylsulfonyl, —C(O)—NH₂, —SO₂—NR⁴R⁵,—C(O)—NH—(C₁-C₈)-alkyl, —C(O)—NH—[(C₁-C₈)-alkyl]₂, wherein R⁴ or R⁵ aredefined above; and wherein n, m, and R¹⁰ are as defined above; in allits stereoisomeric forms and mixtures thereof in any ratio, and itsphysiologically tolerable salts.
 2. The compound of claim 1, comprising

wherein A is carbon or nitrogen, wherein the carbon can be unsubstitutedor substituted by Cl, F, or Br; and R1, R2, and R3 independent from eachother are hydrogen, F, Cl, —O—CH₃, —CH₃, —C(O)—N(CH₂-CH₃)₂, —C(O)—NH₂,or —C(O)—NH—CH₂-piperidine-pyridine, and all stereoisomeric forms andmixtures thereof in any ratio, and all physiologically tolerable saltsthereof.
 3. The compound of claim 2, wherein the compound is4-Chloro-3-[2-(2,4-dichloro-phenyl)-ethoxy]-5-methoxy-N-(3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-ylmethyl)-benzamide.4. A process for the preparation of the compound of claim 2, wherein Wis phenyl comprising a) linking a compound of the formula XI,

wherein R⁰, Q, Q′ and X are as defined in claim 1, are precursor groupsthereof, or are protected by protective groups R^(1′), R^(1″), R^(1′″)and R^(1″″), which protective groups are independently from each other ahydrogen atom; R¹, which is as defined in claim 1, a precursor group; orprotective group; and Y is a nucleophilically substitutable leavinggroup or a hydroxyl group, with a compound of the formula XIIH—NR¹⁰—V—G—M  (XII)  wherein R¹⁰ is a hydrogen atom or —(C1-C4)-alkyl,and V, G and M are as defined in claim 1, or are precursor groupsthereof; and b) reacting the compound of formula XII with a compound ofthe formula XIIIR⁰—Q—X—Q′—W—C(O)—Y  (XIII) wherein R⁰, Q, Q′, X, W and Y are as definedin claim 1, or are precursor groups thereof, and Y is a nucleophilicgroup or a hydroxyl group.
 5. The process of claim 4, wherein R¹⁰, V, Gand M, or the precursor groups thereof, are protected by protectivegroups.
 6. The process of claim 4, wherein R⁰, Q, Q′, X, W and Y, or theprecursor groups thereof, are protected by protective groups.
 7. Theprocess of claim 4, wherein Y is attached to a polystyrene resin.
 8. Apharmaceutical preparation, comprising at least one compound of claim 1.9. A pharmaceutical preparation, comprising at least one physiologicallytolerable salt of a compound of claim
 1. 10. A pharmaceuticalpreparation comprising at least one compound of claim 1, and apharmaceutically acceptable carrier.
 11. A method of modulating bloodcoagulation of fibrinolysis comprising administering one or more of thecompounds of claim 1 in a pharmaceutical preparation to a subject toinhibit factor Xa, factor VIIa, or a combination thereof.
 12. The methodof claim 11, wherein the compound is administered to treat or preventblood coagulation, due to inflammatory response, fibrinolysis,cardiovascular disorders, thromboembolic diseases, restenoses, abnormalthrombus formation, acute myocardial infarction, unstable angina, acutevessel closure associated with thrombolytic therapy, thromboembolism,percutaneous transluminal coronary angioplasty, pathologic thrombusformation occurring in the veins of the lower extremities followingabdominal, knee and hip surgery, transluminal coronary angioplasty,transient ischemic attacks, stroke, disseminated systemic intravascularcoagulatopathy occurring in vascular systems during septic shock,pulmonary thromboembolism, viral infections or cancer, intravascularcoagulatopathy occurring in vascular systems during septic shock,coronary heart disease, myocardial infarction, angina pectoris, vascularrestenosis, adult respiratory distress syndrome, multi-organ failure,stroke and disseminated intravascular clotting disorder, or thromboses.13. The method of claim 12, wherein the compound is used to treatrestenosis following angioplasty-like PTCA.
 14. The method of claim 12,wherein the compound is used to treat deep vein and proximal veinthrombosis occurring following surgery.